1

Office of Research on Women's Health (ORWH)

Research Summaries, FY 2011

Office of the Director

Division of Program Coordination, Planning, and Strategic Initiatives

National Institutes of Health

October 2011
2

Table of Contents

AGING............................................................................................................................................ 4

ALCOHOL AND OTHER SUBSTANCE ABUSE....................................................................... 7

CANCER ........................................................................................................................................ 9

CARDIOVASCULAR DISEASE ................................................................................................ 32

CHRONIC FATIGUE SYNDROME........................................................................................... 38

CRANIOFACIAL......................................................................................................................... 40

DIABETES ................................................................................................................................... 40

DIETARY SUPPLEMENTS/ CAM............................................................................................. 42

GENITOURINARY ..................................................................................................................... 43

GLOBAL HEALTH ..................................................................................................................... 46

HIV ............................................................................................................................................... 59

IMMUNITY/AUTOIMMUNITY................................................................................................. 77

MENOPAUSE.............................................................................................................................. 85

MENTAL HEALTH..................................................................................................................... 93

MUSCULOSKELETAL SYSTEMS............................................................................................ 94

NEUROLOGY/NEUROSCIENCES.......................................................................................... 106

OBESITY/OVERWEIGHT........................................................................................................ 109

PAIN ........................................................................................................................................... 113

PHYSICAL ACTIVITY ............................................................................................................. 116

PREVENTION ........................................................................................................................... 117

REPRODUCTIVE HEALTH/DEVELOPMENTAL BIOLOGY .............................................. 118

RESPIRATORY DISEASES/CONDITIONS............................................................................ 140

RESEARCH DISSEMINATION ............................................................................................... 148
3
4

ORWH RESEARCH SUMMARIES, FY2011

AGING

1-R21-AG-039779-01

Gonadotropins in a female model of age-induced hypertension

Sandberg, Kathryn L

Georgetown University

$230,250

This project is designed to make new discoveries into why age increases blood pressure and the 

prevalence of hypertension across the female lifespan. We will make these new discoveries by 

studying the role of the neglected gonadotropins in the age-induced increase in blood pressure 

that is observed in the Dahl salt-sensitive female rat maintained on a low sodium diet. Animal 

models of female aging are currently limited in number. Hopefully, furthering our understanding 

of this experimental model will lead to a greater use of this animal model in aging research on 

females. Furthermore, by investigating the gonadotropin hormone mechanisms responsible for 

the age-induced increase in blood pressure and hypertension, we may open the door to 

developing new therapeutic treatments for post-menopausal women and women with ovarian 

hormone deficiency - both of which experience marked changes in their gonadotropin profile 

from the ovarian hormone replete state. This project addresses the PA-10-015 by proposing to 

investigate the role and mechanisms of follicle stimulating hormone (FSH) and leutinizing 

hormone (LH) in the age-induced increase in blood pressure (BP) and body weight (BW) 

observed in the female Dahl salt-sensitive (DS) rat. We have previously shown that ovariectomy 

accelerates the age-induced increase in BP and BW in this model and that 172-estradiol (E2) 

prevents these effects. Aging and ovariectomy, however, also result in a marked rise in FSH and 

LH. Though some studies implicate these pituitary hormones in BP regulation, their mechanisms 

of action are poorly understood. These proposed studies will provide key insight into this 

experimental model of female aging and postmenopausal hypertension. Aim 1 will determine if 

preventing the rise in FSH & LH that occurs as a result of ovarian hormone deficiency during 

normal aging from 4 months old (mo) to 12 mo in the female DS rat will attenuate the ageassociated increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative 

stress and activation of the vasoconstrictor arm of the renin angiotensin system (RAS) in 

vascular, renal and adipose tissues. We will also investigate the E2 and progesterone (P4) 

dependency of these pituitary hormone effects. Aim 2 will serve as the corollary to Aim 1 and 

will determine if increasing FSH & LH in young (3-4 mo) female DS rats will result in an 

increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative stress and 

activation of the vasoconstrictor arm of the RAS in vascular, renal and adipose tissues. The 

clinical significance of this research is the insight it will provide into the mechanisms underlying 

the marked rise in the prevalence of hypertension in women as they age and after their transition 

into menopause. 
5

OD-11-301

The Science of Compassion: Future Directions in End-of-Life and Palliative Care

NINR

$2,500

This Summit brought together scientists, researchers, palliative and end-of-life care health 

professionals, educators, policy analysts, members of professional organizations, and members 

of the public. The objectives were to: examine the current status of palliative care and end-of-life 

research, practice, and policy; propose strategies to overcome barriers and ensure scientific and 

methodologic rigor in our research; delineate new action items that galvanize progress in these 

vital areas of science; and, envision and map pathways to ensure a future rich with scientific 

endeavor and achievements. 

1-R01-AG-038467-01A1 

A Biopsychosocial Investigation of Women's Health at Midlife

Upchurch, Dawn M

University Of California Los Angeles

$200,000

Promoting health and well-being, especially as women enter into midlife and early old age is a 

key public heath priority. By better understanding how social, psychological, and lifestyle factors 

(many of which are modifiable) contribute to health during midlife, new information relevant to 

clinical and programmatic interventions will become available. Midlife is a time of significant 

change in women's personal and professional lives. Moreover, health increasingly deteriorates, 

setting the stage for quality of life in later years. The purpose of the proposed research is to 

identify and investigate the longitudinal explanatory pathways that impact 3 important health 

outcomes. We target outcomes that are common and that have high personal and social costs: 1) 

Vasomotor Symptoms; 2) Depressive Symptoms; and 3) Allostatic Load. A distinguishing 

feature of this research is its use of an innovative biopsychosocial model that incorporates 

multiple domains of women's lives and acknowledges the multidimensionality of women's 

health. Specifically, we investigate the impact of: 1) Social Stressors and Social Support; 2) 

Psychological Factors; and 3) Lifestyle Behaviors on each health condition over a 10-year period 

using latent growth curve analysis, longitudinal structural equation models, and longitudinal 

random effects, as appropriate. In so doing, we will identify the specific pathways for both level 

and change over time for each woman for each health outcome. Because we propose that 

multiple aspects of health are linked in complex ways, we will also examine the 

interrelationships between the intervening variables, between the health outcomes, and 

investigate possible feedback between health outcomes and intervening variables. Data are from 

the Study of Women Across the Nation (SWAN) a community-based, 10-year longitudinal study 

of midlife women (aged 42-52 at baseline) designed to characterize the physiological and 

psychosocial changes that occur during the menopause transition. By emphasizing characteristics 

that are potentially modifiable, the proposed research will provide new information relevant to 

clinical and programmatic intervention that may serve to reduce health differentials and promote 

well-being among midlife women. 
6

5R37-AG030481-04

National Social Life, Health, and Aging Project

Waite, Linda J.

National Opinion Research Center

$200,000

They propose to collect a second wave of the National Social Life, Health and Aging Project 

(NSHAP) to obtain data on social networks and social support, marital and cohabitational 

relationships, attitudes, self-reported health and behavior, and cutting-edge biomeasures of 

physical function and health. The crucial contribution of Wave II will be in enabling analyses of 

trajectories; the availability to the community of scholars of such a broad-based, longitudinal 

data set will permit an examination of the health trajectories of older adults and inform new 

approaches to reducing morbidity and preventing disability and dysfunction as individuals age. 

The primary objective of the National Social Life, Health and Aging Project (NSHAP) is to 

establish an innovative, high-quality dataset for use by researchers studying the relationships 

between social processes and health among older adults. Wave I obtained questionnaire and 

biomeasure data on a nationally-representative sample of 3,005 community-dwelling adults ages 

57-85 in 2005/6. They propose to collect a second wave in NSHAP to obtain data on social 

networks and social support, marital and cohabitational relationships, attitudes, self-reported 

health and behavior, and cutting-edge biomeasures of physical function and health. The crucial 

contribution of Wave II will be in enabling analyses of trajectories; the availability to the 

community of scholars of such a broad-based, longitudinal data set will permit an examination of 

the health trajectories of older adults and inform new approaches to reducing morbidity and 

preventing disability and dysfunction as individuals age. They propose to revisit respondents 

four years after their initial interview. Using these data, they can describe and model the 

distribution of changes in health, well-being, social networks, social participation and social 

context. In each case, they shall examine the distributions both for the entire sample and within 

subgroups defined by key sociodemographic characteristics such as gender, race/ethnicity, and 

socioeconomic status. They also propose to augment the sample by interviewing the 

spouse/cohabitating romantic partner. These data will allow us to characterize the impact of 

marital and romantic relationships on health by examining the effects of one person's 

characteristics and behaviors on the health of the other. They will also analyze the partnerships 

themselves, and assess the relationship between characteristics of the partnership, such as 

support, closeness and mistreatment, and the health of each of the partners. In sum, they will 

explore their overarching hypothesis that older adults with strong functioning intimate 

relationships will show more positive (or less negative) health trajectories that those who have 

weaker relationships or lack such relationships altogether.
7

ALCOHOL AND OTHER SUBSTANCE ABUSE

1-R21-DA-027140-01A2

Genes, Gendered Contexts, and Substance Use Outcomes

Verona, Edelyn

University of Illinois Urbana-Champaign

$184,065

Women's drug arrests have increased in the last two decades, whereas men's arrests have 

decreased. Thus, women's drug use has become a significant social problem. An innovative 

aspect of the project is the attempt to identify genetic and environmental factors that are female 

specific for substance use outcomes. Given important sex differences in biology, gene 

expression, and motives, this project can inform psychosocial and pharmacological treatments

for substance use so that they are tailored to address gender-specific issues. It is becoming 

increasingly clear that risk factors for use and trajectories toward desistance may differ 

significantly for men and women (e.g., Westermeyer & Boedicker, 2000). For example, recent 

work has uncovered different effects of monoamine genotypes (e.g., serotonin transporter, 

MAO-A) on male and female psychopathology and behavior (Sjoberg et al., 2007a; Verona, 

Joiner, Johnson & Bender, 2006). In addition, there is evidence that pubertal onset, childhood 

sexual abuse, and intimate partner violence (IPV) constitute unique risk factors for antisocial 

behavior and drug use among women compared to men (Dick, Rose, Kaprio, & Viken, 2000) 

and can predict drug relapse in women many years later in adulthood (Hyman, Garcia, & Sinha, 

2006). Thus, a primary goal of the present application is to identify gender differences in 

biological and environmental risk factors for substance use outcomes as a way of advancing 

nuanced conceptualizations of female drug problems. The current project intends to (1) explore 

various gene by environment (GxE) effects on drug use outcomes, by examining different 

monoamine genes (5HTT, DRD4, MAO-A) and incorporating gendered environmental risk 

factors that are not commonly included in studies of drug use (e.g., intimate partner violence), 

(2) examine the extent to which GxE effects or individual risk factors are specific to substance 

use outcomes in women relative to men, and (3) identify multivariate models involving GxE 

effects and mediators of these effects to predict substance use pathways in men and women. The 

goal is to examine not only GxE effects (e.g., gene-by-abuse, gene-by-IPV) that directly 

influence substance use outcomes, but identify potential mediators (pubertal development, 

internalizing symptoms) in an effort to understand nuanced pathways for female substance use. 

The ultimate goal is to help in the development of tailored interventions to address genderspecific manifestations and etiologies. 
8

2-R01-AA-014441-06A1

Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol

Abdel-Rahman, Abdel A

East Carolina University

$200,000

Given the steady rise in acute alcohol consumption by young women, the proposed research is 

clinically relevant because it: (i) elucidates how estrogen transforms ethanol-evoked cardioprotection into cardiodepression in females; (ii) identifies alcohol use as potential contributor to 

the disappointing outcomes with estrogen in clinical studies; (iii) identifies the estrogen receptor 

subtype(s) implicated in the higher physiological activity of the cardioprotective enzyme, 

myocardial mit-ALDH2 in females. Contrary to conferring cardioprotection in male animals, 

acute ethanol causes estrogen (E2)-dependent myocardial depression in females. Despite 

progress made during the previous award, the molecular mechanisms for this health related 

problem remain unresolved. We hypothesize that E2-mediated accumulation of ethanol-derived 

acetaldehyde (ACA) creates environment conducive to paradoxical transformation of E2 into a 

pro-inflammatory hormone. We will focus on myocardial catalase and mitochondrial aldehyde 

dehydrogenase 2 (mit-ALDH2) because E2 enhancement of their physiological activity confers 

cardioprotection and both enzymes regulate myocardial ethanol-derived ACA balance; catalase 

catalyzes ethanol oxidation to ACA and mit-ALDH2 detoxifies ACA. We hypothesize that E2 

enhancement of myocardial catalase activity could result in higher ethanol-derived ACA. 

Subsequently, competition of higher ACA level with more cytotoxic substrates for mit-ALDH2 

leads to accumulation of cytotoxic aldehydes (oxidative stress and myocardial dysfunction). We 

further hypothesize that E2 mediates these cellular effects via nongenomic estrogen receptor 

(ER) signaling. To test our novel hypotheses, we will employ a multidisciplinary approach that 

encompasses integrative, cellular, molecular and pharmacological studies to address the 

following specific aims. Aim 1 studies will test the hypothesis that enhancement of nongenomic 

rapid ER signaling mediates ethanol-evoked oxidative stress and myocardial depression in 

female rats. Aim 2 studies will elucidate the role of ACA generating (ADH, catalase) and 

aldehyde detoxifying (mit-ALDH2) enzymes in the E2-dependent oxidative stress and 

myocardial depression caused by ethanol. Aim 3 studies will test the novel hypothesis that 

ethanol/ACA- evoked eNOS/nNOS uncoupling plays pivotal role in the paradoxical 

transformation of E2 into proinflammatory hormone in the myocardium and vasculature. These 

studies will further our understanding of the molecular mechanisms for the E2-dependent 

myocardial dysfunction caused by acute alcohol and will allow identification of novel targets for 

new interventions for the treatment/prevention of cardiovascular anomalies caused by alcohol in 

females. 
9

CANCER

5-R03-CA141318-02

Nuclear Pore Complex Architecture and Drug Resistance in Ovarian Carcinomas

Mount Sinai School of Medicine of NYU

$82,208

The proposed studies are concerned with a novel mechanism by which ovarian cancinoma cells 

acquire resistance to cisplatin. While ovarian tumors initially respond well to cisplatin and 

carboplatin, 70 to 80% of advanced stage ovarian cancers will develop resistance to the drug. 

The proposed studies will investigate the role of changes in nuclear pore architecture and 

patterning that may contribute to the acquisition of drug resistance by ovarian cancer cells. 

While ovarian carcinomas initially respond well to treatment with platinum drugs, the majority 

relapse and acquire resistance. In ovarian carcinomas, they have observed reductions of NUP62 

in resected tumor tissue from ovarian carcinomas, and redistribution of NUP62 among 

subnuclear fields of nuclear pore complexes (NPCs). Further, enrichment of NUP62-depleted 

NPCs renders ovarian carcinoma cells resistant to cisplatin in culture. The studies suggest the 

hypothesis that survival advantages conferred by the enrichment of NUP62- and/or NUP214+ 

NPCs may be exploited by tumor cells. To advance this hypothesis, they propose: 1) To 

investigate alterations in the accumulation and distribution of NUP62 and NUP214 in ovarian 

carcinomas, and to decipher how these factors correspond to tumor parameters; and, to 

investigate how changes in expression or accumulation of either NUP62 or NUP214 influences 

distribution of the other nucleoporin among NPCs. 2) To investigate how knockdown of NUP62 

confers resistance to cisplatin; specifically, to decipher how altering the distribution and 

prevelance of NUP62+/NUP214- and NUP62-/NUP214+ NPC populations influence survival 

signaling through NF-:B signaling pathways. The proposed studies impact the basic biology of 

epigenetic regulation and may also illuminate a new approach to improving the prognosis of 

ovarian carcinomas treated with platinum drugs. As the patterning and architecture of NPC 

populations influences the sensitivity of ovarian carcinoma cells to cisplatin, small molecules 

may be developed that modify NPC architecture to enhance its therapeutic effectiveness. These 

agents may be employed to reduce the number of cells that survive and/or become latent in 

response to therapy, and also to chemosensitize relapsed tumors that have acquired platinum 

resistance.

1-R03-CA-156648-01

Vitamin D status, Gene Polymorphism and Breast Cancer Progression/Prognosis

Dorjgochoo, Tsogzolmaa

Vanderbilt University Medical Center

$77,710

Epidemiological studies of sunlight exposure, dietary and supplemental vitamin intake, and 

genetic variants have mostly focused on the role of vitamin D in mitigating breast cancer (BC) 
10

risk, and a few studies have investigated the effect of vitamin D, particularly vitamin D gene 

polymorphisms, and only one of circulating vitamin D, on BC prognosis or survival. Although 

there is some evidence that vitamin D pathway genes and circulating 25(OH)D together play a 

role in mitigating BC risk, no data yet exist on their combined effect on BC progression; thus, 

the proposed study aims to fill this research gap by evaluating the association of circulating 

vitamin D and its pathway gene polymorphisms with BC prognosis. The results of this study 

could potentially lead to the development of new preventive and therapeutic strategies that can 

be applied to BC patients. The association of vitamin D deficiency, or low levels of circulating 

vitamin D, with increased risk for cancers, including breast cancer (BC), has received extensive 

attention. Experimental studies have shown that vitamin D has many anti-cancer properties, 

including anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulation effects. Less 

attention has been paid to the role of vitamin D deficiency on BC prognosis and survival 

outcomes. Studies have shown that circulating vitamin D and polymorphisms in genes regulating 

vitamin D metabolism and signaling are both associated with BC risk, however, we know less 

about associations with BC prognosis. A few studies have linked low circulating vitamin D 

levels with prognostic factors for BC outcome, such as advanced disease or metastasis. Only one 

study directly evaluated the association between vitamin D status and BC survival, and no study 

has investigated this association in relation to vitamin D polymorphisms. We propose to address 

these questions in a prospective cohort of Chinese women with BC and test three hypotheses: 1) 

Circulating vitamin D level will predict BC progression and prognosis (recurrence, metastasis, 

overall or disease-specific death) after cancer treatment; 2) Genetic polymorphisms in vitamin D 

metabolism and signaling pathway genes affect circulating vitamin D level and its bioavailability 

in BC survivors; and 3) Circulating vitamin D and vitamin D gene polymorphisms together 

affect BC progression and prognosis. The proposed study will use resources from the Shanghai 

Breast Cancer Survival Study (SBCSS) and the Shanghai Breast Cancer Genome-Wide 

Association Study (GWAS). We will include 2,073 women newly-diagnosed with invasive BC 

and aged 20-74 years at the time of diagnosis, who have both blood samples for assessing 

circulating 25(OH)D and genotype information. Information on cancer diagnosis and 

conventional treatment, breast cancer recurrence, and causes of death will be verified through 

medical chart reviews. We will evaluate the effect of circulating vitamin D level and its 

combined effect with polymorphisms in the vitamin D pathway genes on BC progression and 

prognosis using appropriate statistical methods and controlling for known prognostic factors. The 

Mendelian Randomization (MR) method will be used to re-assess this association. Breast cancer 

survivorship is recognized as a critical component of cancer- related public health programs. The 

proposed study aims to fill a gap in our knowledge by evaluating the associations of circulating 

vitamin D and vitamin D pathway gene polymorphisms with breast cancer prognosis. This study 

will expand our understanding of the role of "Vitamin D status" and related pathway gene 

polymorphisms in BC prognosis. The study results could potentially lead to the development of 

new preventive and therapeutic strategies that can be applied to BC patients. In addition, the 

research could help determine if chemoprevention clinical trials with vitamin D should be 

considered for BC patients at high-risk for disease progression. 
11

1-R21-CA-143619-01A1

Videoconference CBT for Rural Breast Cancer Survivors with Cognitive Complaints

Ferguson, Robert J

Eastern Maine Medical Center

$170,338

The proposed study seeks to advance knowledge concerning the value and use of health 

information technology (HIT) to expand access of care to rural and underserved populations. 

Teleconference technology allows real-time interaction with clinicians across vast geographical 

distances. This makes possible the delivery of important treatments to cancer patients who 

otherwise may not be able to benefit from such care due to geographical distance. Cognitive 

dysfunction associated with cancer chemotherapies can have a dramatic effect on cancer survivor 

quality of life and is recognized as a growing survivorship problem. However, the etiology of 

chemotherapy- related cognitive change is unknown, with no current broadly validated 

treatment. The PI is developing a brief cognitive-behavioral therapy (CBT; Memory and 

Attention Adaptation Training; MAAT) designed to help cancer survivors self-manage and cope 

with daily memory failure. Preliminary research suggests MAAT may improve self-reported 

daily cognitive failures and verbal memory performance, and survivors rate it with strong 

satisfaction, but more research is needed. The proposed research aims to evaluate a revised and 

more intense version of MAAT (increase from 4 to 8 visits) delivered through videoconferencing 

technology to aid rural breast cancer survivors with chemotherapy-related cognitive complaintsindividuals with geographic and cost barriers to survivorship services. MAAT will be compared 

to a videoconference supportive therapy (ST). Thus, this study seeks to evaluate feasibility of 

MAAT delivered through videoconference technology. Participants. 48 women treated for stage 

I, II, or IIIa breast cancer with chemotherapy-related cognitive complaints, 6 months past last 

chemotherapy and who do not have other neurologic or psychiatric histories, or untreated anxiety 

or mood disorders will be enrolled. Intervention. MAAT-Video (MAAT-V) will consist of 8 

weekly one-hour group sessions consisting of 2-4 members each linked by videoconferencing 

devices at up to 6 rural outreach clinics. Multiple participants can be seen by the clinician and 

participants can also see each other from different sites. ST is identical in length and time of 

sessions (8 one-hour sessions), but is more passive and less instructional than MAAT. Design. 

Breast cancer survivors will be randomized to either MAAT-V or ST. Survivors will be 

evaluated for self-reported impact of cognitive problems on quality of life, anxiety about 

cognitive problems, functional wellbeing, and on brief telephone-based neuropsychological tests 

of memory at 3 time points: pre-treatment, post-treatment and 2-month follow-up. Statistical 

analyses will consist of a 2 X 3 (baseline, post-treatment and follow-up), repeated measures 

analysis of variance with dependent measures listed above and a planned comparison approach 

to reduce risk of spurious findings. Type of chemotherapy, age, education, estimated IQ, fatigue, 

and other factors will be evaluated as possible covariates. Clinically significant change on 

outcome measures will be evaluated using the reliable change index (RCI). Satisfaction will be 

assessed with 0-8 Likert-type ratings. A qualitative analysis of 20 randomly selected participants 

will be completed to assess practicality of MAAT-V. Significance. Study results will advance 

knowledge of the feasibility of MAAT delivered through videoconference to improve breast 

cancer survivor quality of life, especially in rural, underserved areas. 
12

1-R21-CA-155932-01A1

Survivorship Care Planning and Communication for Rural Breast Cancer Survivors

Geiger, Ann M.

Wake Forest University Health Sciences

$160,950

Experts have recommended that the often difficult transition from active treatment to cancer 

survivorship care be eased by preparation and communication of a survivorship care plan. Our 

study will gather information about rural-, suburban- and urban-residing cancer survivors' needs 

and preferences for survivorship care planning and communication. This information will help us 

design and evaluate a care planning process designed specifically to accommodate the needs of 

rural-residing survivors while also meeting the needs of suburban- and urban-residing survivors. 

The Institute of Medicine and others have strongly recommended survivors exiting active 

treatment receive a comprehensive survivorship care plan addressing surveillance, late effects 

symptoms, psychosocial needs, and general health maintenance, as well as indicating which 

providers will handle which components of the plan. Despite this recommendation, survivorship 

care planning and communication are often inadequate, leaving survivors confused and uncertain 

about their care. In addition, little is known about communication- related barriers to 

survivorship care, which may be of particular concern for rural-residing survivors who often live 

at some distance from their oncology specialist(s) and have limited primary care access. To 

reduce confusion and uncertainty, and to avoid duplication of medical effort, we envision a 

formal planning and communication process that integrates patient preferences with 

recommendations from multiple providers to generate a comprehensive survivorship care plan. 

[We believe effective implementation of this process requires a clinically-oriented individual like 

a nurse, nurse practitioner, physician assistant, or physician to facilitate and coordinate 

communications between survivors and their primary care and oncology specialty providers.] 

Our goal is to generate information needed to create and evaluate a process designed specifically 

to accommodate the needs of rural-residing survivors while also meeting the needs of suburban 

and urban survivors. Thus we aim to: (1) describe breast cancer survivors' knowledge about, 

perceived importance of, and barriers to survivorship care planning and communication; (2) 

assess survivors' current and preferred communication with oncology specialists and primary 

care providers about their survivorship care plans; and (3) explore the relationship between 

current survivor and provider survivorship care planning and communication with survivors' 

cancer-related uncertainty and quality of life. All data will be collected via a survey relying 

heavily on questions drawn from previously validated instruments and administered via hard 

copy mail, on-line or telephone interview. Our analytic approach will include descriptive 

statistics, correlation, and regression modeling. Both this proposal and the resulting testable 

intervention of a clinical model of survivorship care planning and communication will 

substantially advance our understanding of cancer survivorship care, particularly for ruralresiding breast cancer survivors. 
13

1-R21-AT006376-01

Acupuncture for Aromatase Inhibitor-Related Arthralgias in Breast Cancer Patients

Hershman, Dawn 

Columbia University Health Sciences

$200,000

Aromatase inhibitors have been shown to improve the survival time of women diagnosed with 

breast cancer. However, many women discontinue this life extending therapy due to unwanted 

side effect such as joint pain. This study tests will confirm the findings of a pilot randomized trial 

of acupuncture for decreasing aromatase inhibitor-induced joint pain. We propose a multicenter 

randomized, sham-controlled study of 200 breast cancer survivors. Third generation aromatase 

inhibitors have been shown to be superior to tamoxifen in improving disease free survival, 

decreasing distant and local recurrence rates and decreasing incidence of contra-lateral breast 

cancer in women with early stage hormone receptor positive breast cancer. However, up to 50% 

of women on AI report symptoms of debilitating musculoskeletal pain and joint arthralgia that 

can lead to noncompliance and early discontinuation, thereby impacting survival. Our previous 

phase II randomized study (n=40) showed that acupuncture administered twice weekly for 6 

weeks compare to sham acupuncture improve AI induced joint pain/stiffness as measured by 

modified Brief Pain Index short form (mBPI-sf) worse pain score by 50%. The proposed phase 

III randomized, sham controlled, blinded, multi-centered clinical trial will look at the effects of 

acupuncture on joint pain/stiffness that started or increased since initiation of AI in 200 women 

with Stage I-III breast cancer. Women will be recruited from four institutions and randomized to 

either true acupuncture or sham acupuncture administered twice weekly for 6 weeks follow by 

maintenance weekly acupuncture or sham acupuncture for 6 weeks. True acupuncture sessions 

will consists of standardized full body and joint specific point prescription and the NADA 

auricular protocol. The sham acupuncture treatment will consist of superficial needling at full 

body and joint specific point prescriptions that do not correspond to any true acupuncture points. 

The primary hypothesis is that acupuncture administered twice weekly for 6 weeks then weekly 

for 6 weeks will reduce joint pain/stiffness in women with AI induced arthragia as measured by 

mBPI-SF scores at 6 weeks compared to sham acupuncture. Secondary endpoints will assess 

whether weekly maintenance true acupuncture from week 6 to week 12 will maintain the effects 

seen at week 6 as measured by mBPI-SF score at 12 weeks and whether true acupuncture will 

have a durable effect as measure by mBPI-SF score at 24 weeks, compared to sham acupuncture. 

Other secondary endpoint (to be evaluated at baseline, 6, 12 and 24 weeks) include 1) additional 

assessment of joint pain/stiffness and functional status via self administered questionnaires 

(Western Ontario and McMaster Universities Osteoarthritis (WOMAC), Modified Score for the 

Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) 

and Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society 

International criteria (OMERACT-OARSI), 2) quality of life assessment via the self 

administered questionnaire Functional Assessment of Cancer Therapy- Breast/Endocrine 

subscale (FACT-B/ES), 3) analgesic use, 4) functional testing (grip strength and "timed get up 

and go' for lower extremity") and 5) exploratory hormonal and inflammatory biomarkers. This 

study will be the first large multi-center center intervention trial looking at the effects of 

acupuncture on AI induced arthragia in women with breast cancer. 
14

1-R03-CA-156626-01

Advanced Glycation End Products And Colorectal Cancer Risk In Women

Jiao, Li 

Baylor College Of Medicine

$98,397

The importance of the AGEs/RAGE axis in CRC development has not been investigated in 

women. The findings from this study may lead to identification of potentially modifiable risk 

factors for CRC and biomarkers for monitoring disease progression. Advanced glycation endproducts (AGEs) are sugar adducts to proteins that form and accumulate under conditions of 

hyperglycemia. Binding of AGEs with the receptor for AGEs (RAGE) promotes oxidative stress 

and inflammation and soluble RAGE can block such effects. This application sets out to examine 

whether AGEs increase colorectal cancer risk and soluble RAGE play a protective role in 

colorectal cancer development among postmenopausal women in the Women's Health Initiative 

Observational Study. Advanced Glycation End-products (AGEs) are a heterogeneous group of 

compounds formed via the nonenzymatic glycation of lipids, proteins and nucleic acids. AGEs 

form endogenously during normal metabolism, and exogenously from foods processed at a high 

temperatures and tobacco smoking. N5- (carboxymethyl)-lysine (CML)-AGE is one of the best 

characterized AGEs. The accumulation of AGEs in the human tissues accelerates under 

hyperglycemia. AGEs trigger oxidative stress and inflammation by interacting with the receptor 

for AGEs (RAGE). Soluble RAGE (sRAGE) neutralizes the reactions mediated by the RAGE 

and therefore, acts as an anti-inflammatory factor. We recently reported that levels of sRAGE 

significantly predicted a lower risk of colorectal cancer (CRC) in Finnish male smokers. The role 

of AGEs and sRAGE in CRC development has not been investigated in women. We hypothesize 

that AGEs contributes to CRC development while sRAGE exerts a protective effect. We propose 

a case-cohort study that builds upon three NIH-funded studies conducted within the Women's 

Health Initiative (WHI) Observational Study of a cohort 93,676 postmenopausal women. The 

proposed study includes 425 incident CRC cases and 791 randomly selected subcohort 

participants. The study has three specific aims: 1) To examine the association between baseline 

fasting circulating levels of CML-AGE, sRAGE, and the sRAGE/CML ratio and risk of 

subsequent development of CRC; 2) to examine the independent predictors of circulating levels 

of CML-AGE and sRAGE among the subcohort participants, including age, body mass index, 

alcohol use, daily average intake of nutrients (e.g., carbohydrate nutrients and fatty acids), and 

tobacco smoking; and 3) to explore the inter-relationships among circulating levels of CMLAGE, sRAGE and serological markers of insulin resistance, inflammation and estradiol on the 

risk of CRC. The availability of pre-diagnostic bio-specimens and exposure information, as well 

as previously measured analytes, makes this study highly feasible and efficient. The long- term 

goal of this research is to elucidate a modifiable pathway, AGEs/RAGE, that may connect 

environmental exposure (e.g., dietary intake), inflammation, and insulin resistance with CRC 

etiology and prognosis. 
15

1-R21-CA-149531-01A1

Decisional Aid Intervention for Women Considering Breast Reconstruction

Manne, Sharon L

Fox Chase Cancer Center

$200,000

The decision whether to pursue breast reconstruction (BR) can be challenging. Women must 

weigh the importance of potential benefits of the procedure and their personal values and 

preferences against the risks associated with the procedure and decide what type of 

reconstruction to have should they pursue it. We propose to develop a web-based decision aid for 

women being offered BR, evaluate its usability, feasibility, and acceptability, and gather 

preliminary data on its impact of BR knowledge, values, decisional conflict, preparedness, BR 

interest, and anxiety. The decision whether to pursue breast reconstruction (BR) can be 

challenging. Women must weigh the importance of potential benefits of the procedure and their 

personal values and preferences against the risks associated with the procedure and decide what 

type of reconstruction to have should they pursue it. The decision is typically made in a stressful 

circumstance, which is immediately after the initial diagnosis of breast cancer. Complicating 

matters is the fact that there is evidence to suggest that there are variable rates of satisfaction 

with the cosmetic outcomes of BR. Outcomes may not be in line with what the patient initially 

expected. BR can be a difficult decision made under stressful circumstances and women may not 

be as well- informed about the long-term effects as they could be. When patients are faced with 

treatment decisions for which personal values and quality of life issue play a role and there are 

multiple treatment choices, decision support in the form of decision aids can be helpful to the 

process of making a well-informed choice. Decision support aids are a strategy used as an 

adjunct to practitioners' counseling to facilitate their understanding of the treatment options, the 

advantages and disadvantages of each option, consideration of the personal importance they 

attach to the benefits and risks of each alternative, and to encourage active participation with the 

care provider in deciding which option to pursue. We propose to develop a web-based DA for 

women being offered BR. We will accomplish this in three phases. Phase 1 is a developmental 

phase where the basic DA content is developed by the study team with input from patients who 

have undergone BR, were offered BR and decided against it, or are considering BR. We will 

include input from minority women, women over 65 years of age, and less educated women, 

who have less access to BR. Phase 2 consists of gathering feedback terms on the DA prototype 

from women who have undergone BR, women who were offered BR and chose not to have it, 

and women who are considering BR. Again, feedback from minority women, women over 65 

years of age, and less educated women will be included. The BR Decision Aid (BRDA) will then 

be finalized. Phase 3 will be a usability and feasibility pilot test of the DA with a sample of 

women considering BR. The study has one primary aim and two secondary aims. The primary 

aim is to evaluate the usability and feasibility of a decisional aid to assist women with making 

the decision to undergo BR. The secondary aims are to examine the acceptability of the BRDA 

and to provide preliminary data on the impact of BRDA on BR knowledge, values, decisional 

conflict, preparedness, BR interest, and anxiety. 
16

1-R03-CA-162869-01

Understanding the Cervical Cancer Health Gap for Women in Jail

Ramaswamy, Megha

University of Kansas Medical Center

$80,361

The public health impact of this study is that it will inform interventions that reduce cervical 

health morbidity and mortality for an already disadvantaged group, women involved in the 

criminal justice system. This study will tell us not only about the chasm between women's 

understanding of Pap events and actual medical encounters, but will also speak more generally to 

this population's experience with health care access, given their movement in and out of the 

criminal justice system. Women in the criminal justice system are four-five times as likely to 

have cervical cancer compared to non- incarcerated women. Some have attributed this disparity 

to difficulty in follow-up of abnormal Paps, but little is known empirically about why women 

involved in the criminal justice system have low abnormal Pap follow-up rates. The objective of 

this application is two-fold: to understand the interpretation of abnormal Pap events and their 

subsequent follow-up from the perspective of incarcerated women; second, to interpret women's 

abnormal Pap events and follow-ups based on a review of their medical records. The validation 

of women's accounts of abnormal Pap follow-up (or lack thereof) with medical chart review will 

provide an understanding as to why some women do not gain access to follow-up care. Thus, we 

will be able target interventions to address this documented gap in women's understanding of 

abnormal Pap events versus actual events. To meet this objective, first we will conduct focus 

groups and in-depth interviews with 40 women in a Kansas City county jail about abnormal Pap 

screening and subsequent follow-up events. Studying women's experiences with abnormal Paps 

and follow-up may provide clues as to their cervical cancer screening knowledge and the 

processes by which women actually seek out cervical cancer prevention services given their 

movement in and out of jails. Second, we will ask the 40 women previously interviewed for 

permission to access their medical records, in order to investigate whether incarcerated women's 

self-report of abnormal Pap and follow-up events matched actual medical records of these 

events. This aim will allow us to gauge women's understanding of Pap events, validate the 

medical barriers that women faced in trying to gain access to follow- up care, and demonstrate 

the feasibility of assessing health care access through medical chart review for this high-risk 

population. This project has significance for public health impact by providing insight into how 

to address the cervical cancer burden for women involved in the criminal justice system. This 

project is innovative in its goal of assessing incarcerated women's understanding of abnormal 

Pap events and validating their understanding with medical record review. Study findings will 

contribute to the development of an intervention that attempts to close the cervical cancer health 

gap between women involved in the criminal justice system and their sisters in the "free" world. 
17

5-U19-GM-061388-12

Pharmacogenetics of Phase II Drug Metabolizing Enzymes

Weinshilboum, Richard M

Mayo Clinic

$240,292

Breast cancer is the most frequent cancer of women and depression is the most common major 

psychiatric illness. Drugs are available to treat both of these serious illnesses, but many patients 

fail to respond and some suffer serious adverse drug reactions. The Mayo Clinic 

Pharmacogenomics Research Network (PGRN) will apply modern pharmacogenomic techniques 

to help make it possible to "individualize" the drug therapy of breast cancer and depression. The 

Mayo PGRN is an integrated, multidisciplinary, pharmacogenomic research effort based on a 

decades-long focus at Mayo on the pharmacogenetics of phase II (conjugating) drug 

metabolizing enzymes. The Mayo PGRN began by applying a "genotype-to-phenotype" research 

strategy that included, sequentially, gene resequencing, functional genomic, mechanistic and 

translational studies. During the present funding cycle, the Mayo PGRN has also incorporated 

the use of genome-wide techniques and pharmacogenomic model systems, with a special 

emphasis on functional mechanisms responsible for genetic effects on drug response. They have 

used that approach to study the pharmacogenomics ofthe endocrine therapy of breast cancer and 

selective serotonin reuptake inhibitor (SSRI) therapy of depression - research that grew out of the 

contribution of phase II enzymes to the biotransformation of the estrogens that play such an 

important role in breast cancer and biotransformation ofthe neurotransmitters that are central to 

the pathophysiology and treatment of depression. Recently, they have performed 

pharmacogenomic genome-wide association (GWA) studies of breast cancer, and they will soon 

perform similar studies of the SSRI therapy of depression. They propose to continue this 

genome- wide focus during the next funding cycle, with both clinical and model system GWA 

studies of the drug therapy of breast cancer and depression, always including replication as well 

as functional and mechanistic studies. They also propose two "Network Resources", one 

designed to provide access to "Next Generation" DNA sequencing for all PGRN Centers and the 

other focused on pharmacogenomic ontology. In summary, the studies in this application build 

on Mayo PGRN strengths in DNA sequencing and functional genomics - while incorporating 

genome-wide techniques - to provide insight into the role of inheritance in variation in the 

efficacy and side effects of drugs used to treat breast cancer and depression. 
18

1-R21-CA-160917-01

Role of the Fractalkine Signaling in Epithelial Ovarian Carcinoma (EOC)

Barbolina, Maria V

University Of Illinois At Chicago

$ (NCI funded this ANSWHR award)

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy mainly due to metastasis 

and is an unsolved problem in public health. In this proposal we will characterize the 

requirement for chemokine signaling in progression of ovarian carcinoma, because 1) according 

to our preliminary data it could play a major role in all stages of the ovarian carcinoma 

metastatic cascade, and 2) chemokines and their receptors are effective drug targets proven to 

work in the clinic in treatments of other diseases. Epithelial ovarian carcinoma (EOC) is a 

leading cause of death from gynecologic malignancies. Peritoneal metastasis is an unsolved 

clinical problem in treatment of EOC. Currently used therapeutic approaches are not specific to 

EOC metastasis and are inefficient at keeping patients in remission. Thus, targeting the prometastatic pathways could provide improved opportunities to increase survival. In our approach 

to find new targets we searched among pathways that satisfy the following criteria: 1) play a 

major role in EOC progression; 2) have proven to be effective targets for treatments of other 

diseases. Chemokine signaling is essential for cancer cell migration, proliferation, adhesion, and 

invasion, i.e., properties that are necessary for a successful development of metastasis. In this 

application we will characterize fractalkine pathway as crucial for the development of metastasis 

in EOC and determine potential usefulness of its main players, chemokine fractalkine (CX3CL1) 

and its receptor, fractalkine CX3CR1, as novel targets for future therapies aimed at prevention 

and retardation of metastatic spread. Our preliminary data show that primary and metastatic 

specimens of human EOC are highly positive for CX3CR1, while normal ovarian surface 

epithelium in non-diseased control subjects is CX3CR1-negative. Moreover, we show that EOC 

cells can migrate in CX3CR1-dependent manner to CX3CL1. Furthermore, in our pilot 

experiments increase of CX3CR1 expression in EOC cells led to formation of more tumors of 

larger size in a xenograft EOC mouse model. Chemokines are promising drug targets. Moreover, 

chemokine receptors are the G protein coupled receptors, a class of proteins that are effective 

drug targets covering an estimated 30% of FDA approved drugs. Such drugs have been proven to 

work in the clinic, and new drugs against CX3CL1 and CX3CR1 are currently under 

development. CX3CL1/CX3CR1 is a uniquely suitable drug target because the interaction 

between the chemokine and its receptor is very specific, and there are no other chemokine 

ligands activating CX3CR1, in contrast to other chemokine/receptor pairs that display high 

cross-reactivity. Thus, drugs directed at either CX3CR1 or CX3CL1 will likely to affect only the 

CX3CL1/CX3CR1 axis. Based on our preliminary data and published literature our hypothesis is 

that CX3CL1/CX3CR1 axis is required for homing metastatic EOC cells to the peritoneum and 

facilitation of metastatic spread by supporting cell adhesion and migration. To test this 

hypothesis we propose two aims. In Aim 1 we will determine the requirement of 

CX3CL1/CX3CR1 in adhesion to peritoneal mesothelial cells and underlying extracellular 

matrix using cell culture models and previously developed by us EOC metastasis-specific culture 

conditions. Adhesion is one of the main initial steps of the metastatic colonization of the 

peritoneum. In Aim 2 we will characterize the requirement for CX3CL1/CX3CR1 in 

development of EOC metastasis in vivo using a xenograft mouse model. 
19

1-R21-CA-161713-01

Confirmation Studies Of Blood Based Biomarkers Of Risk For Breast Cancer

Hanash, Samir M

Fred Hutchinson Cancer Research Center

$ (NCI funded this ANSWHR award)

There is a substantial need to identify women at increased risk for developing breast cancer. 

Prior studies by the applicants using in-depth quantitative technology to profile circulating 

proteins in the blood for potential risk markers have identified many potential markers of risk 

among post-menopausal women that subsequently developed breast cancer. These novel 

candidate risk markers for breast cancer require additional studies for their verification. The 

objectives of this proposal to do additional verification studies of the candidate biomarkers in an 

independent set of women from the Women's Health Initiative and to determine the relevance of 

these markers as mediators of the risk for breast cancer associated with post-menopausal 

hormone therapy. There is a substantial need to identify biomarkers of risk for breast cancer. An 

in-depth quantitative proteomics approach was applied to the analysis of plasmas that were 

collected prior to a diagnosis of breast cancer in search for candidate markers of risk for this 

disease. The samples were obtained from the Women's Health Initiative (WHI) cohort and 

consisted of women diagnosed with breast cancer within seven years of blood collection and 

controls matched for age, self-reported ethnicity, hysterectomy status and enrollment date. In 

parallel studies proteomic profiling was applied to blood specimens obtained at baseline and 

following one year of hormone therapy (HT) with conjugated equine estrogen (CEE) or 

CEE/MPA (medroxyprogesterone acetate). Extensive proteomic analyses identified a large 

subset of circulating proteins that were affected by HRT, and has also yielded a set of breast 

cancer risk marker candidates that merit additional validation studies. Interestingly some of the 

risk candidates were also affected by HRT and thus may contribute to elucidation of breast 

cancer risk associated with CEE/MPA therapy. In aim 1, we propose to conduct a confirmation 

study of risk markers identified using an independent set of WHI participants from the WHI 

hormone therapy trials who developed breast cancer and matched controls. Of the 14 candidates 

to be subjected to confirmation studies, eight have ELISAs available that would allow their 

assay. The remainder of the candidates would be subjected to confirmation using Multiple 

Reaction Monitoring mass spectrometry. A second aim consists of evaluating the identified risk 

markers as mediators of hormone therapy effects on breast cancer. To that effect plasmas 

collected at baseline and at 1-year of HT in the CEE and CEE/MPA trials will be utilized to 

determine changes in concentration of risk marker candidates in cases and in matched controls. 

The proposed project has the potential to contribute clinically relevant breast cancer biomarkers 

to identify women at increased risk and to clarify breast cancer risk associated with 

postmenopausal hormone therapy. 
20

5-R21-CA-135570-02

Estrogen and Skin Cancer

Oberyszyn, Tatiana M

Ohio State University

$ (NCI funded this ANSWHR award)

There is an increase societal pressure in the US to remain young looking. Several studies carried 

out in post-menopausal women demonstrate the effectiveness of topical estrogen in reversing the 

signs of aging including thinning, dryness and wrinkling. As a result younger pre- and perimenopausal women are turning to topical creams containing estrogen as anti-aging lotions. Our 

preliminary studies using female Skh-1 hairless mice found a significant increase in the number 

of tumors in mice treated topically with estrogen immediately following UVB exposure 

compared to mice treated with vehicle control. These data indicate that increased levels of 

estrogen in the skin combined with UV exposure may act to enhance initiation and promotion of 

UV- induced skin cancers. These findings also suggest that the use of lotions and creams 

containing estrogenic compounds on sun exposed sites by younger women may be contributing 

to the increase in the number of skin tumors being diagnosed in women under the age of 40. The 

current studies are designed to determine the effect of topical estrogen treatment of previously 

UVB exposed skin on tumor development and progression from benign lesions to frank 

malignant squamous cell carcinomas. Americans live in a culture that glorifies youth. According 

to market researcher FIND/SVP, the anti- aging products market is expected to hit $56 billion by 

2007. Studies in post-menopausal women have found that hormone replacement therapy is 

effective at reversing the dryness and wrinkling that affects aging skin. Based on these studies, 

there is increasing interest in the use of topical creams containing hormones such as estrogen to 

prevent or reverse some of the normal cutaneous aging processes in younger pre-menopausal 

women. While exposure to these creams may be beneficial cosmetically, the effect of applying 

estrogen to sun exposed sites for prolonged periods of time, on skin cancer development is not 

known. Our preliminary studies using female Skh-1 hairless mice found a significant increase in 

the number of tumors in mice treated topically with estrogen immediately following UVB 

exposure compared to mice treated with vehicle control. These data indicate that increased levels 

of estrogen in the skin combined with UV exposure may act to enhance initiation and promotion 

of UV-induced skin cancers. These findings also suggest that the use of lotions and creams 

containing estrogenic compounds on sun exposed sites by younger women may be contributing 

to the increase in the number of skin tumors being diagnosed in women under the age of 40. 

Most studies have examined the effects of topical or systemic estrogen on the skin in postmenopausal women, however the reality is that younger pre-menopausal women are applying 

topical estrogen containing creams on their faces previously exposed to UV light to 

prevent/reverse the signs of aging. Two specific aims are proposed to test the hypothesis that 

topical estrogen application to previously UVB exposed skin accelerates skin carcinogenesis. 

Studies in specific aim 1 will use the Skh-1 hairless mouse murine model of UVB induced skin 

carcinogenesis to determine the effects of clinically used topically applied estrogen (Estrogel(R)) 

on UVB induced skin tumor development in previously UVB exposed female skin of intact (premenopausal) and ovariectomized (post-menopausal) mice. Studies in specific aim 2 will 

determine the effects of topically applied estrogen (Estrogel(R)) on UVB induced skin tumor 

progression in female Skh-1 skin of intact and ovariectomized mice. The studies carried out in 
21

these aims will determine whether topical estrogen increases the number of UVB induced skin 

tumors that develop and also whether it differentially enhances the progression of benign UVBinduced tumors to malignant squamous cell carcinomas in intact (pre-menopausal) and 

ovariectomized (post-menopausal) mice. 

N01-CP11005

Efficacy of HPV-16/18 Vaccine Against Oral HPV Infections 

Kreimer, Aimee 

NCI Intramural Research Project

$50,000

With support from ORWH, we previously expanded specimen collection in our Costa Rica trial 

to permit the evaluation of vaccine efficacy at sites other than the cervix. It is now known that 

HPV causes a subset of H&N cancers, cancers of the oropharynx in particular. Given this, we 

are now in the process of evaluating efficacy of the vaccine to protect against HPV infections in 

the oral cavity. Testing of oral specimens for HPV DNA using sensitive methods is ongoing and 

expected to be completed in FY11. Once testing is completed, data preparation and analysis will 

follow. ORWH support could be used to support the analytical efforts associated with this 

evaluation.

N01-CP11005

Natural History and Clinical Implications of Anal HPV Infections 

Kreimer, Aimee 

NCI Intramural Research Project

$200,000

HPV is known to be involved in the development of the majority of anal cancers. Anal cancers 

are more common in women than in men, and are increasing in the United States. We previously 

noted that anal HPV infection is common (about 30%) among young adult women in our 

population in Costa Rica. Understanding of the natural history of anal HPV infections and the 

clinical significance of anal HPV positivity is limited. In particular, information on rates of 

persistent HPV given infection and the clinical implications of these persistent infections and any 

associated lesions is lacking. We have the opportunity to evaluate these issues within our cohort 

of women in Costa Rica. ORWH support could be used for activities associated with the followup and testing of women in our cohort previously found to have an HPV infection.
22

N01-CP11005

Gallbladder Cancer Pilot Study

Hsing, Ann; Koshiol Jill

NCI Intramural Research Project

$150,000

Gallbladder cancer is one of the few non-gynecological tumors known to occur with higher 

frequency in women than in men. The highest rates of this cancer (particularly in women) are 

observed in Chile. Investigators in the Infections and Immuno-epidemiology Branch (IIB) are 

evaluating the feasibility of conducting a case-control study of gallbladder cancer in Chile to 

better understand the causes of this disease. As currently envisioned, the initial pilot effort will 

define whether such a study would be successful at identifying and enrolling cancer cases, 

controls with gallstones (an important precursor for this cancer) and controls form the general 

population. We are working with well established investigators in the region with a proven track 

record of conducting epidemiological investigations to maximize the likelihood of success. A 

case-control study of gallbladder cancer in Chile would permit us to elucidate the role of obesity 

(and metabolic syndrome more generally), diet, infections, immunological responses, and genetic 

susceptibility factors in the etiology of this tumor. This study could have important public health 

implications, since cholecystectomies are currently being recommended for women for the 

prophylaxis of gallbladder cancer in this high risk area. A better understanding of the causes of 

this disease could lead to the development of better and less aggressive preventative measures 

against this disease.

N01-CP11005

Comparison of the Impact of Vaccination with Gardasil and Cervarix

Hildesheim, Allan

NCI Intramural Research Project

$50,000

Two vaccines are currently licensed for the prevention of HPV-infections and their associated 

cancers - Gardasil and Cervarix. While both vaccines are based on HPV virus-like particles, 

they differ with respect to the HPV types included in the vaccine, the adjuvant used, and 

potentially by the ability to protect against infections with HPV types other than those included 

in the vaccine formulation. Given these differences, it is currently unclear whether the overall 

impact afforded by use of these two vaccines will be similar or not, and to the extent that they 

differ by how much. Support from ORWH will be used for analyses aimed at addressing this 

question.
23

N01-CP11005

Immune Markers of Protection by HPV Vaccination

Safaeian, Mahboobeh; Hildesheim, Allan

NCI Intramural Research Project

$100,000

One of the stated aims of the publically-funded HPV vaccine trial in Costa Rica is to investigate 

potential immunological markers and mechanisms of protection by the HPV vaccine that might 

assist in the identification of minimal levels required for protection and also assist in the 

generation of second generation and/or other vaccines in the future. At the HPV Immunology 

Laboratory affiliated with our group, we have developed assays to help monitor vaccine immune 

responses after vaccination in our cohort. Support from ORWH will help activities at the 

laboratory to evaluate immune responses and to evaluate markers of protection against both 

homologous and non-homologous HPV types. It will also assist in our immunological follow-up 

of individuals receiving different numbers of doses, to further understand our recent finding that 

vaccine efficacy is observed when fewer than three doses are administered.

3-P30-CA-016058-35S1 

Cancer Center Support Grant

Caligiuri, Michael A

Ohio State University

$5,000

Title: Cancer Health Disparities Research among Appalachian Women

Principal Investigators: Michael Caligiuri and Electra Paskett

Women in Appalachia Ohio suffer a disproportionate burden of cancer, including higher cancer 

incidence and mortality rates for cervical, colon, and lung cancer compared to cancer rates for 

women in Non-Appalachian region of Ohio. The proposed supplement would support a 

Conference to strengthen the existing community and academic infrastructure to increase 

community-based participatory research (CBPR) capacity within Appalachia Ohio to address the 

cancer health disparities among women in Appalachia Ohio. Plans for this proposed Conference 

have been developed in collaboration with established community partners and identified needs 

among women in this community. The Conference will consist of two related educational efforts: 

a Seminar designed to build upon our past efforts to increase knowledge about cancer health 

disparities among women in Appalachia, and a Workshop to support the development of joint 

research efforts between academic researchers and community partners to address these 

disparities. The Seminar will feature presentations about CBPR programs conducted to address 

cancer in Appalachian women by scientist/academic researchers, as well as evidence-informed 

interventions conducted by community partners. The agenda for the Workshop will help build 

academic-community partnerships through interactive sessions on the important components of 

CBPR and strategies to ensure academic-community partnerships effectively address cancer 

health disparities and cultural barrier among underserved women in Appalachia Ohio. 

Collectively, this conference will maximize learning, group interaction and networking among 

academic researchers at the Ohio State University and established community partners through 

the Appalachia Community Cancer Network (ACCN) to enhance joint CBPR efforts through 

academic-community partnerships with a goal of reducing cancer health disparities among 
24

women in Appalachia. The proposed conference will strengthen the academic-community 

infrastructure at the OSUCCC to increase CBPR capacity within Appalachia to address defined 

cancer health disparities including elevated rates of cervical, colon and lung cancers among 

women in Appalachia. OSUCCC will plan, implement and evaluate this conference with a clear 

vision of the needs and values of this community. 

3-P30-CA-047904-23S1 

Cancer Center Support Grant

Davidson, Nancy E

University Of Pittsburgh

$15,000

Pilot study of somatic mutations and gene fusions in ovarian cancer

Principal Investigators: 

Adrian V. Lee, Ph.D., Aleksandar Milosavljevic Ph.D. and Xiaosong Wang, M.D.

Ovarian cancer is the largest cause of death from female reproductive tract cancers. In 2010, 

there were an estimated 21,880 new cases and 13,850 deaths. The high rate of mortality from 

ovarian cancer is in part due to diagnosis at an advanced stage. Indeed, up to 70% of ovarian 

cancers have metastasized at diagnosis, and only 30% of women with this diagnosis can expect 

to live 5 years. In stark contrast, 20% of ovarian cancer is detected at an early stage (and within 

the ovary) resulting in an excellent 90% survival rate (2). While the last 30 years has seen 

dramatic reductions in mortality rates from several cancers (e.g. a 30% reduction in breast cancer 

mortality), the mortality rate from ovarian cancer has seen only a modest improvement. We 

propose a pilot analysis of ovarian cancer data publicly available from the Cancer Genome Atlas 

to: 1) Identify novel fusion genes which might serve as novel diagnostic, prognostic, and 

therapeutic targets, and 2) identify patterns of somatic mutations which may highlight novel 

pathways for therapy. This pilot project will involve a unique collaboration between 

investigators in the newly developed Women’s Cancer Research Center (a collaboration between 

the University of Pittsburgh Cancer Institute (UPCI) and the Magee Women’s Research 

Institute), and bioinformaticians in the Dan L Duncan Cancer Center at Baylor College of 

Medicine. TCGA is a rapidly providing an outstanding wealth of information on molecular 

alterations in many cancers (http://cancergenome.nih.gov/). However, similar to most other 

studies, this information (data) needs translation into knowledge, particularly the clinical 

relevance of the identified changes. The ovarian cancer dataset at TCGA is one of the most 

mature (http://tcga-data.nci.nih.gov/tcga/). 587 matched and tumor tissues have been analyzed. 

Assays have included expression arrays (mRNA and miRNA), DNA copy number and SNP 

arrays, methylation marks, and massively parallel sequencing. UPCI is a major contributor to 

TCGA. For ovarian cancer, UPCI provided approximately 120 matched normal and tumor tissue, 

and about 62 passed QC and are in the final dataset. Our goal is to perform an initial pilot 

analysis of molecular changes in the ovarian cancers and validate them in the index cases we 

have here at UCPI. Validated somatic alterations will then be examined in larger data sets and 

correlated with clinical features and outcomes.
25

3-P30-CA-072720-13S9 

Cancer Center Support Grant

Dipaola, Robert S

UMDNJ-Robert Wood Johnson Medical School

$15,000

Title of project: The influence of gender on the relationship between mental health and 

smoking.

Principal Investigator: Cristine D. Delnevo, Ph.D.

Individuals with past-month mental health problems are approximately twice as likely to smoke 

as other persons and suffer a greater burden from tobacco-related morbidity and mortality, 

including cancer. In addition, women are overrepresented among smokers with poor mental 

health and preliminary data from our research team suggests that relationship between smoking 

and poor mental health may differ by gender. We propose analyses of three public health 

surveillance data systems to explore the issue of smoking and mental health by gender. The 

Behavioral Risk Factor Surveillance System (BRFSS), the National Survey on Drug Use and 

Health (NSDUH), and the National Epidemiologic Survey on Alcohol and Related Conditions 

(NESARC) all address both tobacco use and mental health. Accordingly, we will conduct 

secondary data analyses to achieve these specific aims: 1) document the prevalence and 

demographic correlates of tobacco use and nicotine dependence among individuals with poor 

mental health and 2) evaluate whether there is an interaction effect by gender for smoking and 

poor mental health. We hypothesize that women with mental health problems, particularly 

certain psychiatric disorders, will be at higher risk for current smoking and nicotine dependence 

than men. More research is needed to examine gender disparities in the context of mental health 

and smoking. Thus, the significance of this proposed research is its potential to generate a better 

understanding of smoking and mental health by gender to inform and direct tobacco control 

efforts which are vital to reducing tobacco-caused cancers in women.

3-P30-CA-138313-03S1

Medical University of South Carolina - Cancer Center Support Grant

Kraft, Andrew S

Medical University Of South Carolina

$15,000

Title: Disruption of ceramide synthesis by CerS2 depletion as a tool to increase breast 

cancer sensitivity to taxane therapy

Principal Investigators: Stefka D. Spassieva and Lina M. Obeid

Paclitaxel is widely used for breast cancer treatment, but the success of the chemotherapy can be 

hindered by patients not responding or developing resistance; therefore, it is important to 

discover new strategies to increase sensitivity or to overcome the resistance to taxane therapy, 

which will improve the chances of breast cancer patients to become diseases-free. With our pilot 

project proposal, we address the possibility of developing such a new strategy by investigating 

breast cancer sensitization and resistance to paclitaxel in the context of the ceramide pathway. 

The potential of the ceramide pathway to sensitize to paclitaxel treatment was recently shown in 

a functional genomics screen . In that screen, several members of ceramide pathway are shown 
26

to alter theresponse of chemotherapy resistant cancer cell lines (including a breast cancer cell 

line) to paclitaxel treatment. Of particular interest for our current study is one member of the 

ceramide pathway, ceramide synthase 2 (CerS2), which when down-regulated by siRNA was 

shown to increase the sensitivity of cancer cells to paclitaxel. Moreover, our recent study showed 

that depletion of CerS2 resulted in alteration of ceramide metabolism, activation of the Unfolded 

Protein Response (UPR), and induction of autophagy. In addition to the findings from our 

laboratory, the functional genomics screen showed that paclitaxel treatment of cancer cells can 

activated the UPR as well. Moreover, a very recent study found that the elevation of 78-

kDaglucose-regulated protein (GRP78), an UPR marker, can serve as a predictor for the 

effectiveness of the taxane treatment in breast cancer patients. Accordingly, our working 

hypothesis is that aberrant ceramide synthesis in CerS2 depleted breast cancer cells disrupts ER 

homeostasis, which when combined with paclitaxel treatment, enhances ER stress and leads to 

cell death. 

3-P30-CA-016359-33S1

Yale Comprehensive Cancer Center

Lynch, Thomas James

Yale University

$20,000

Title: Testing the Feasibility of a Nurse Patient Navigation Intervention in Lung Cancer

Principal Investigator: Ruth McCorkle, Ph.D., R.N.

This single blind, randomized clinical trial is designed to 1) describe the feasibility of 

implementing a Nurse Patient Navigation (NPN) intervention that addresses patient and 

caregiver questions, symptoms, psychosocial needs, and facilitates timely, coordinated care, and 

2) compare the impact of the NPN Intervention with an attention control group at Smilow Cancer 

Hospital with newly diagnosed advanced lung cancer patients on quality of life outcomes, 

utilization of health care services, and perceptions of care transitions. Thirty-two women newly 

diagnosed with advanced lung cancer will be randomized to either the NPN intervention or 

attention control groups. The 14 contact NPN intervention includes provision of information, 

problem-solving strategies, coordination of care, and support for patients that will enhance their 

QOL and increase their perception of care transition. Outcome data will be collected on patient 

quality of life outcomes, health care utilization, and care transition at baseline, 1, and 3months 

post diagnosis. The primary goal of this application is to assess the feasibility of implementing a 

Nurse Patient Navigation (NPN) intervention for newly diagnosed advanced lung cancer 

patients. The intervention will be implemented and evaluated with women undergoing diagnostic 

and staging procedures, including surgery, at Smilow Cancer Hospital (SCH).
27

5-R01-CA-126841-03

Regulatory T Cell Function in Ovarian Cancer

Moysich, Kirsten B

Roswell Park Cancer Institute Corp

$15,000

Title: Single Nucleotide Polymorphisms (SNPs) in the anti-inflammatory cortisol pathway 

and the risk of ovarian cancer

Principal Investigator: Kirsten Moysich

Ovarian cancer remains the most lethal gynecological cancer, due to the fact that the majority of 

patients present with advanced disease at diagnosis. The established risk factors such as parity, 

use of oral contraceptive (OC) pills, use of NSAIDS, and talc exposure, suggest a role of 

ovulation and inflammation in the etiology of ovarian cancer. More than 90% ovarian tumors 

arise from the surface epithelium[1] lined by a single layer of squamous to cuboidal cells 

covering the entire ovarian surface[2]. This epithelium is breached during each ovulation leading 

to an inflammatory reaction [3-4]. Persistence of inflammation associated with ovulation can 

cause genetic damage and trigger carcinogenesis. Cortisol, a major anti-inflammatory steroid 

plays a significant role in attenuating inflammation, thereby reducing the risk of ovarian 

carcinogenesis. Levels of cortisol in the ovarian epithelium rise significantly prior to ovulation. 

Ovarian tumor cells have significantly reduced expression of genes in the cortisol pathway 

compared to those in normal ovarian epithelial cells [5]. We, therefore, hypothesize that single 

nucleotide polymorphisms (SNPs) in genes involved in the cortisol pathway are associated with 

the risk of ovarian cancer due to potential variation in anti-inflammatory cortisol response. SNPs 

in these candidate genes have not been adequately captured in a recent GWAS of ovarian cancer. 

Thus a thorough investigation of genetic variability in this highly biologically plausible pathway 

is warranted. We propose to utilize data and samples from an existing study of 800 incident 

epithelial ovarian cancer cases and 800 population-based controls recruited in Pennsylvania, 

Ohio, and New York between 2003 and 2008. Our first aim is to evaluate the association of 

SNPs in the cortisol pathway and the risk of ovarian cancer. We will identify functional and tag 

SNPs using public databases (Hapmap, Genome Variation Server, dbSNP). Logistic regression 

models will be used to estimate the associations between these SNPs and risk of ovarian cancer. 

Our second aim is to evaluate the association of SNPs in the cortisol pathway with the severity of 

disease (grade and stage of ovarian cancer) at diagnosis. Finally, in our exploratory aim, we 

propose to conduct a preliminary analysis on a subset of patients to evaluate the associations of 

SNPs in the cortisol pathway and disease-free and overall survival. We have substantial followup time (at least five years) on a large subset of the study sample. We will use Cox proportional 

hazards ratios and Kaplan-Meier survival probabilities to analyze the data. Dr. Moysich 

maintains active national and international collaborations with ovarian cancer researchers and 

will have access to a number of study samples for replicating significant genetic associations. 

The results of this study will provide a valuable insight into the etiology of ovarian cancer by 

uncovering an important anti-inflammatory pathway. It could also potentially help to direct 

therapeutic research and develop strategies to screen high risk women for prognosis
28

3-R01-CA-118136-05S2

Stress, Immunity & Cervical Cancer: Biobehavioral Outcomes of a Randomized Trial

Wenzel, Lari 

University Of California, Irvine

$15,000

Telomeres are structures composed of repetitive DNA sequences that cap the end of 

chromosomes and play a critical role in preserving genomic stability and integrity. Short 

telomeres have been associated with hematologic and solid tumor malignancies. But more 

recently, in a pivotal epidemiologic study shortened telomere length was associated with 

development of primary malignancy and mortality after controlling for other factors typically 

linked with cancer , supporting an etiologic role for shortened telomeres in cancer development 

and progression. Telomere length in leukocytes has been documented to be responsive to a 

number of stimuli and in some cases can result in lengthening of telomeres . Recently, an 

accelerated rate of telomere loss in peripheral blood mononuclear cells (PBMCs) has been 

described in chronically stressed populations (3-6), begging the question can modulation of 

chronic stress result in changes in telomere length or rate of telomere loss? We have used 

archived PBMC specimens from a recently completed randomized clinical trial, in which our 

group demonstrated that a psychosocial telephone counseling (PTC) intervention significantly 

improved quality of life (QOL) and biobehavioral parameters associated with chronic stress in a 

cervical cancer survivor cohort (7), to establish the capacity to examine longitudinal associations 

between telomere length and other parameters of the psychoneuroimmune axis associated with 

chronic stress. We established methodologies for evaluating telomere length from PBMC 

subsets: T cell (CD3, CD4 and CD8), B cell (CD19) and monocyte (CD14) cellular subsets using 

the Flow-FISH assay. In this small sample set (n=30 subjects, for which specimens were 

available), a longitudinal decrease in psychological distress was associated with increased 

telomere length within the T cell subset population (CD3) (r = -0.565, p = 0.018). Given the 

previously published association between improved QOL and increased Th1 immunologic 

stance, it was reassuring that increased telomere length in the CD3 T cell subset was also 

associated with a shift toward a Th1 immune profile (r = 0.582; p = 0.023). These data provide 

proof of concept for the longitudinal analyses of telomere length from cryopreserved PBMCs 

and support telomere length as a novel component of biobehavioral paradigms, and provide 

preliminary data in support of exploring associations between stress response and telomere 

length. Thus, we propose to examine a larger sample set, over a more substantial longitudinal 

time frame, by conducting these analyses on PBMCs that are being collected from an ongoing 

larger randomized clinical study (5RO1CA118136-04 Stress, Immunity & Cervical Cancer: 

Biobehavioral Outcomes of a Randomized Trial) (target 250 subjects) testing biobehavioral 

differences between those counseled compared to those not counseled, to evaluate the 

downstream physiologic effects of improved QOL and decreased stress responses. This study 

would have provocative implications for the association between the psychoneuroimmune axis, 

telomere dynamics and survivorship outcomes in an underserved female population and as an 

area of scientific priority, directly addresses the examination of social factors, health behaviors 

and their interaction with biology in a testable, comprehensive interdisciplinary model of health 

affecting cancer treatment, control and survivorship. 
29

OD-11-302

Characterization of Novel Viruses from Human Genitals 

NCI Intramural—Center for Cancer Research 

$25,000

Principal Investigators: Christopher B. Buck and Diana V. Pastrana

Next-generation sequencing projects characterizing the ribosomal genes of bacterial species have 

revealed that humans are stably colonized by a staggering diversity of distinct microbial species. 

Since viruses lack universally conserved gene products, such as ribosomal sequences, 

comprehensive elucidation of the diversity of the viral constitutents of the human “metagenome” 

has been more challenging. This proposal is aimed at developing a more detailed catalog of viral 

sequences chronically shed into the human genital tract. By expanding our knowledge of the 

human genital virome, we hope to gain insight into several diseases. For example, about a dozen 

known species of human papillomavirus (HPV) are thought to play a role in essentially all cases 

of cancer of the uterine cervix, as well as roughly 20-60% of vulvar and vaginal cancers. Several 

known HPV species have also been suggested as possible causal factors underlying a fraction of 

miscarriages. The fraction of gynecological cancers and miscarriages that are not attributable to 

known HPVs might theoretically be linked to previously unidentified members of the 

papillomavirus family or to other unidentified viruses that may commonly inhabit the female 

genital tract. Our laboratory has previously utilized amethod known as rolling circle 

amplification (RCA) to identify previously unknownHPVs and other viral families that are 

common constituents of skin virome of healthy human subjects. This previous work also 

revealed a wide variety of DNA sequences with little or no homology to any sequences available 

in GenBank. For the current project, we have obtained genital swab specimens from HIV 

infected individuals, who might be expected to harbor a higher burden of genital viral flora. 

Next-generation sequencing of these samples has revealed an overwhelming number of sequence 

fragments with no clear homologs, as well as sequence fragments with distant homology to 

known HPV genera. Several intriguing classes of sequence show limited resemblance to viral 

families that have previously only been found in plants or fungi. These preliminary data warrant 

continuation of the project, which will involve cloning and sequencing the complete genomes of 

unidentified new genera of HPVs, as well as full-length sequencing of candidate novel human 

virus families.

OD-11-302

Urinary Estrogens and Estrogen Metabolites in Relation to Objective Measures of Physical 

Activity among Controls in the NCI Polish Breast Cancer Study 

Dalla, Cher; Gierach, Gretchen 

NCI Intramural, Division of Cancer Epidemiology and Genetics 

$15,000

The prevalence of obesity remains elevated in the United States, particularly among women. 

According to data from the National Health and Nutrition Examination Survey, 35% of women 

in the United States were classified as obese in 2007-2008 with a BMI of ≥ 30 kg/m2. More 

specifically, the prevalence of obesity among women ages 40-59 was 38.2% during this time 

period. This is of particular importance given the consistent association between obesity and an 
30

increased risk of cancer among postmenopausal women, including cancers of the breast, 

endometrium, and colon. Additionally, numerous epidemiological studies suggest that higher 

levels of physical activity may reduce postmenopausal breast cancer risk . However, the 

mechanisms underlying these observed associations and the relationship between energy balance 

and biomarkers, such as estrogens and their metabolites, remain unclear. Promoting physical 

activity may have important implications for reducing breast cancer risk and other cancers, but to 

date, our understanding of the underlying mechanisms is limited in several respects: 1) lack of 

objective measures of physical activity in studies of sex steroid hormones; 2) incomplete 

assessment of estrogen metabolites, which are suggested to differentially contribute to breast 

cancer risk and 3) small sample sizes and limited covariate information in previous studies. We 

aim to better define relationships between physical activity and estrogen metabolites among 

postmenopausal women by leveraging the existing resources of the population-based NCI Polish 

Breast Cancer Study. We propose a novel approach to examine the association between 

accelerometer measured physical activity and a more comprehensive estrogen hormone profile 

among population-based controls (n=685) from the Warsaw site of the Polish Breast Cancer 

Study. Objective physical activity measures, collected through the use of an accelerometer, 

quantify the duration and intensity of activity on a minute-by-minute basis, without the limitation 

of self-report bias. This study addresses health behaviors and their interaction with biology and 

their role in cancer prevention, two areas of scientific priority outlined by the Institute of 

Medicine (IOM). Findings from this study will extend our biological understanding of the effects 

of physical activity, a modifiable health behavior, on estrogen metabolism and may contribute to 

translational efforts to improve cancer prevention and risk prediction for women.

OD-11-302

Symposium: Opportunities and Changes in Cancer Research among Women in Developing 

Countries 

Ji, Bu-Tian; Chow, Wong Ho 

NCI Intramural, Division of Cancer Epidemiology and Genetics 

$5,000

Studies of cancer risks and survival in different populations with diverse exposures, cancer 

surveillance and care, and varying incidence and mortality patterns broaden the opportunities for 

discoveries of cancer causes and prognostic factors. With rapid changes in economic conditions 

and industrial development in Asia, particularly in countries such as China, South Korea, and 

Japan, lifestyle and environmental exposures in this region have also undergone substantial 

changes over the past few decades. These changes are reflected in the cancer incidence patterns 

of these countries. For instance, in Shanghai, China, incidence rates of cancers that are 

traditionally high in developing countries, such as esophageal squamous cell carcinoma, and 

cancers of the stomach and liver, have declined precipitously over the past few decades. In 

contrast, cancers of the colon and breast have increased substantially. In fact, among women 

under age 50 years, breast cancer is the most rapidly rising malignancy in Shanghai. Similar 

cancer incidence patterns are being reported in other areas of Asia. Changes in lifestyle such as 

fewer number of children and later age at first child birth, decreased physical activity both at 

work and at home, and increasing intake of meat, fat, and processed foods are believed to have 

contributed to the upward trends of colon cancer and breast cancer among women in Shanghai 
31

and some other areas in Asia. Likewise, the relatively high and perhaps worsening air pollution 

in many Chinese cities have kept the lung cancer incidence rates relatively high among women 

in these areas, despite an extremely low rate (<5%) of cigarette smoking among Chinese women. 

Occupational exposure to industrial agents also tends to be higher than similar industries in the 

United States. Furthermore, almost all women have held jobs outside the home, with the 

majority being employed in blue collar jobs with greater chance for exposure to industrial 

carcinogens. The changing environment and cancer occurrence in Asia provide an unparalleled 

opportunity for collaborative research into cancer causes and gene-environment interaction in 

cancer development. Since the early 1980s, the pioneering efforts of several investigators in 

DCEG and other NCI Divisions have led to many fruitful collaborations in China. With more 

rapid changes in recent years in China and other parts of Asia, there are enhanced opportunities 

for further collaboration. The purpose of the proposed workshop is to review current status of 

collaborative cancer research, to discuss research ideas and identify new opportunities for 

research, and to plan future collaborative research directions. The proposed workshop will invite 

investigators from the U.S., China, and other Asian countries who have conducted collaborative 

research in Asia to share their research results, with the goal of identifying gaps and 

opportunities for further collaboration. The proposed location for this one-day workshop is 

Shanghai, China, in order to minimize travel by most invited investigators from Asia. The 

workshop is tentatively planned for June 28, 2011, and will be opened to local academic 

participants. The workshop is to be jointly sponsored by the NCI and the Shanghai Cancer 

Institute. The requested funding from the Office of Science Planning and Assessment will 

support meeting arrangements (i.e., meeting site, technical support, and refreshments) and travel 

for a limited number of invitees from Asia. A summary report and abstract of presentations will 

be delivered after the workshop. However, the ultimate achievement will be the continuing 

dialogue and new research collaborations among some meeting participants.

OD-11-302

Workshop: Postpartum Breast Remodeling, Lactation and Breast Cancer Risk: Towards 

Improved Assessment and Prevention 

Sherman, Mark

NCI Intramural, Division of Cancer Epidemiology and Genetics 

$5,000

The goal of this workshop is to critically assess key questions related to postpartum events and 

the pathogenesis of breast cancer. The postpartum period is an important focus of research 

related to promoting child health. In contrast, comparatively few studies have taken advantage of 

the repeated medical contacts during this period to conduct research on maternal health, and in 

particular, to develop strategies for reducing breast cancer mortality. The postpartum period is 

temporally related to pregnancy and breastfeeding, two poorly understood factors related to 

breast cancer risk. In addition, this window offers the unique opportunity to collect and analyze 

breast milk, which may enable non-invasive analyses of breast cells and fluids among young 

healthy women. Therefore, this time in the life course represents a promising interval for 

investigating the pathogenesis of early onset breast cancer and for developing strategies for risk 

assessment and prevention of these tumors. Accordingly, the objective of this workshop is to 

assemble experts to critically assess our current understanding of postpartum re-modeling of the 
32

breast, lactation, and breast cancer and to identify gaps in knowledge and resources that would 

be required to advance research on this topic. A recent comprehensive review of breastfeeding in 

developed countries produced by the AHRQ (Ip et al Breastfeeding Medicine (2009) concluded 

that breastfeeding reduces maternal risks for breast cancer and for type 2 diabetes mellitus, 

which elevates breast cancer risk. Risk stratification of young women may allow the 

development of evidence-based screening intervals at later ages or identification of candidates 

for prevention interventions.

CARDIOVASCULAR DISEASE

Y2-OD-1456-01:

Role of Androgen and Estrogen Receptor Signaling in Pulmonary Arterial Hypertension 

(Bench to Bedside) 

Danner, Robert; 

Clinical Center/NIH; NIDDK; University of Pennsylvania

$110,000

Idiopathic pulmonary arterial hypertension (IPAH), a subtype of plexogenic pulmonary 

arteriopathy (PAH), is a rare disorder associated with poor survival. Despite consistent 

epidemiological evidence demonstrating a 2 to 4 fold female predominance in IPAH, the 

underlying mechanisms for this imbalance are unclear. Endothelial dysfunction resulting from 

1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the 

so-called two-hit hypothesis, appears to play a central role both in the pathogenesis and 

progression of PAH. Inflammation may drive this dysfunctional endothelial phenotype, 

propagating cycles of injury and repair in genetically susceptible patients with IPAH and patients 

with disease associated PAH (e.g. scleroderma, HIV, and sickle cell disease). Histologic 

specimens from patients with IPAH reveal the presence of inflammatory cells, including 

macrophages and T- and B-lymphocytes, within classic plexiform lesions that are the hallmark of 

PAH. Pulmonary artery endothelial cells (PAECs) in PAH orchestrate the recruitment of 

inflammatory cells as well as secreting pro-inflammatory and pro-coagulant cytokines into the 

circulation. Patients with IPAH have higher levels of circulating IL-1β, IL-6, P-selectin and Eselectin in comparison to healthy controls. Therefore, targeting PAEC inflammation may 

interrupt the cycles of injury/inflammation and repair that contribute to progressive increases in 

pulmonary vascular resistance in patients with PAH, and thereby delay or prevent right 

ventricular failure and death. Both estrogen and testosterone promote vasodilatation and affect 

vascular inflammation through binding to estrogen (ER) and androgen receptors (AR), 

respectively, members of the nuclear receptor (NR) family of transcription factors. However, the 

interaction between sex hormone signaling and IPAH-associated vascular injury/inflammation is 

not understood. Many NRs inhibit inflammation through a trans-repression mechanism that 

recruits co-repressor proteins to promoter NFκB and AP-1 binding sites in a tissue and target 

gene specific manner. Using an in silico bioinformatics approach, we found that the androgen 

receptor (AR) is relatively over-expressed in primary human endothelial cells compared to 

phagocytic leukocytes. Initial work in our laboratory using EA.hy926 cells, a human endothelial 
33

line, demonstrates that dihydrotestosterone (DHT) can suppress TNFα-induced VCAM1 mRNA 

expression, while spironolactone, a mixed mineralocorticoid receptor and AR antagonist 

currently used in PAH for advanced right heart failure, was found to inhibit NFκB signaling. We 

hypothesize that AR and ER differentially modulate endothelial inflammation in IPAH and this 

may in part explain the female predominance of this disease. Here, the effects of AR and ER 

signaling on endothelial dysfunction and inflammation will be investigated in cell culture 

models. Patients with PAH will be recruited to the NIH to investigate novel MRI-based methods 

to improve clinical phenotyping and as part of a pilot feasibility study on the effects of early 

spironolactone on endothelial inflammation in vivo.

3-R01-HL-089847-03S1

Endogenous Cardiac Repair in Humans

Margulies, Kenneth 

University Of Pennsylvania

$40,000

In recent successful experiments, we have isolated resident stem/progenitor cells from human 

hearts and induced their in vitro differentiation into contracting cardiac myocytes. Building on 

these findings, this research is focused on characterizing selected subpopulations of these 

stem/progenitor cells with an emphasis on elucidating their capacity for replication and 

differentiation into functioning cardiac myocytes. We contend that insights into the 

cardiomyogenic potential of endogenous cardiac stem/progenitor cells will promote progress 

towards therapeutic cardiac regeneration with or without cell therapy per se. Until recently, the 

heart has been viewed as a terminally differentiated organ with no capacity for new cardiac 

myocyte (CM) formation. This view appears to be incorrect, in that we and others have been able 

to isolate cardiac-derived progenitor cells (CDPCs) from human myocardium. Extending these 

results, our recent studies indicate that cells expressing the stem cell surface marker c-kit can be 

isolated from human hearts immediately after explantation and subsequently induced to 

differentiate into CM via short-term co-culture with neonatal rat ventricular myocytes (RVMs). 

Though we typically find more c-kit+ cells usually in failing vs. nonfailing hearts, the need to 

replace these failing hearts via transplantation highlights the inadequacy of native cardiac repair 

mechanisms. Based on these findings, our broad working hypothesis is that increased c-kit+ 

CDPCs in failing human hearts include both lineage-negative c-kit+ and c-kit+/CD45(dimmoderate) cells that are each capable of new myocyte formation in vitro. In this context, the 

objective of this proposal is to quantify and characterize these distinct subpopulations of 

stem/progenitor cells within human hearts with an emphasis on elucidating their functional 

capacity for replication and CM differentiation. Our first aim is to identify what types of 

stem/progenitor cells are present in normal and failing human hearts. We will define distinct 

stem/progenitor subpopulations based on immunotyping of disaggregated myocardial cells with 

fluorescence microscopy and flow cytometry and perform complementary studies in tissue 

sections from the same hearts to define their distribution. Our second aim is to characterize 

replicative capacity of the selected CDPC subpopulations based on a combination of static assays 

(telomere length, telomerase activity and and p16INK4a expression) and functional assessment 

of proliferation rates. Our third aim is to characterize the cardiac myogenic potential of selected 

CDPC subpopulations derived from human hearts. These studies will define the rates and 
34

frequency of CM differentiation for sorted subpopulations under stardardized co-culture 

conditions, define whether cell contact is required for induction of CM differentiation by 

neonatal rat myocytes and identify secreted factors (chemokines or growth factors) that promote 

or augment rates of in vitro CM diffentiation in selected CDPC subpopulations. The 

clinical/therapeutic significance of this proposal is based on the premise that insights into the 

proliferative and cardiomyogenic potential of endogenous cardiac stem/progenitor cell 

subpopulations will promote progress towards therapeutic cardiac regeneration with or without 

cell therapy per se. 

3-R01-HL-060666-11

Metabolism During Mechanical Circulatory Support in the Developing Heart

Portman, Michael A

Seattle Children's Hospital

$20,000

Infants and children are often supported by a bypass pump during or after heart repair. This study 

will determine hormone and nutritional strategies to support the immature heart while supported 

by this type of mechanical circulation. In particular, we will examine how thyroid hormone 

influences how the heart generates and uses important energy molecules. Extracorporeal 

membrane oxygenation (ECMO) remains the primary method of long term support after 

myocardial stunning caused by cardiac surgery in infants and children. ECMO often provides a 

bridge to recovery in these young patients. However, ventricular unloading as occurs with 

ECMO also promotes cardiac atrophy. Therefore, this therapy can be counterproductive in 

initiating reparative processes leading to restoration of normal cardiac function. Substantial 

abnormalities in hormonal homeostasis, such as decreases in circulating levels of thyroid 

hormones, occur during both shorter term cardiopulmonary bypass (CPB) and longer term 

ECMO. Disruptions in thyroid hormone homeostasis can alter substrate utilization, deplete citric 

acid cycle intermediates, possibly effecting net protein turnover. Additionally, we have noted 

that pyruvate supplementation can improve cardiac function after CPB in immature pigs. 

Thyroid hormone supplementation promotes pyruvate entry into the citric acid cycle, and 

promotes citric acid cycle intermediate conversion to amino acids. These findings suggest that 

appropriate substrate supplementation can improve protein synthesis and functional recovery 

after protracted mechanical circulatory support. We will study a prolonged period of mechanical 

circulatory support (ECMO) in the immature pig, an appropriate translational model for children 

undergoing these procedures. We will test the primary hypothesis: in the developing heart 

cardiac dysfunction due to ventricular unloading (ECMO)-is a consequence of impaired substrate 

utilization due at least in part to disruptions of thyroid hormone homeostasis. Targeted metabolic 

interventions in combination with thyroid hormone supplementation will minimize the adverse 

effects of ECMO and thereby improve longer term functional recovery and survival. Using NMR 

and GC-MS, we will determine if metabolic abnormalities, which lead to cardiac dysfunction 

and atrophy can be treated by supplementing the citric acid cycle with pyruvate. We will 

determine if pyruvate combined with thyroid hormone supplementation (T3) a) accelerates 

pyruvate flux, b) reduces oxidation of amino acids, c) stimulates transamination to amino acids 

and d) improves cardiac function and protein synthesis after a prolonged period of ventricular 
35

unloading. We will also determine if supplementation of medium chain fatty acids with and/or 

without thyroid hormone similarly supports the heart. 

OD-11-287

Clinical research united in successful enrollment – workshop on clinical trials. 

NHLBI 

$9,964

As our health care system moves to expand access, evidence based-medicine and the need for 

well designed and conducted clinical trials become paramount. The goal of this workshop was to 

provide recommendations to NHLBI and co-sponsors in three key areas that impact clinical trial 

enrollment: 1) Public and professional awareness and acceptance of clinical trials, 2) Human 

subject research policies, guidelines, and reimbursement, and 3) clinical trial enrollment 

experience and practice, in order to optimize enrollment in clinical trials. 

1-R21-HL-093631-01A1

Sex Differences in Molecular Heterogeneity of Cardiac Repolarization

Bett, Glenna C L

State University of New York At Buffalo

$ (NHLBI funded this ANSWHR award)

This proposal seeks to understand the basis of sex-differences in the electrical activity and 

pharmacological sensitivity of the heart. Sex is an often overlooked fundamental clinical 

variable, which can have a significant impact on health outcome. Understanding the basis of 

cardiac sex differences offers the opportunity for translational advances in the identification of 

therapeutic targets with the potential to improve patient outcomes and improve healthcare for 

both men and women. This proposal is a revised application in response to an RFA for R21 

applications to advance Novel Science in Women's Health Research. Although heart disease is 

the #1 killer of both Men and Women in the US, only 27% of participants in cardiac clinical 

trials are women. In basic research, most experiments are performed on male animals only. It is 

therefore not surprising that little is known about the basic molecular mechanisms even for such 

clinically important fundamental factors such as why female cardiac action potentials are longer 

than male action potentials. Even less is known about why 70% of congenital Long QT 

syndrome patients are women, and why women are at particular risk for drug induced 

arrhythmias. This application proposes to advance science in women's health research by 

determining the molecular basis for sex dependence and hormonal regulation of IKr and IKs, the 

two major repolarizing currents in heart. This research is strongly hypothesis driven, and the 

overall guiding hypothesis is that differences in the electrophysiological and pharmacological 

profile of IKr and IKs are responsible for sex differences in cardiac repolarization. This is a 

departure from the current concept that it is purely the action potential duration that is the key 

determinant of arrhythmia susceptibility. We are proposing that the important factor is not the 

absolute action potential length, but the relative contribution of IKr and IKs, combined with their 

pharmacological sensitivities that are a critical factor in arrhythmogenesis. The alpha subunits of 

IKr and IKs are HERG and KCNQ1 respectively. However, their relative expression, 

electrophysiological and pharmacological profiles are determined by the presence of KCNE 
36

ancillary subunits. Our hypothesis is that hormonal regulation of these subunits is the major 

factor in determining differences between male and female myocytes. We will test this 

hypothesis by determining IKr and IKs electrophysiological profile in human cardiomyocytes 

derived from male and female induced Pluripotent Stem Cells (iPSCs) from skin cells, as well as 

ventricular myocytes from male, female and ovariectomized (OVX) guinea pigs. We will also 

expose myocytes to estradiol and testosterone to test the direct effects of hormones on currents 

and use molecular interventions to determine subunit specificity. We will use the experimental 

data to develop mathematical models of human and guinea-pig action potentials which contain 

hormonal regulation of IKr and IKs. We will use these models to make predictions about the 

dynamic behavior of repolarization (e.g., restitution, QT prolongation and pharmacological 

sensitivity) which can be tested in our experimental human and guinea pig models. These 

innovative simulation studies will provide testable hypotheses which are readily applicable to 

electrophysiological studies in humans. 

1-R21-HL-109527-01

Cardiovascular Disease Biomarkers and Mediation of Hormone Therapy Effects

Prentice, Ross L

Fred Hutchinson Cancer Research Center

$ (NHLBI funded this ANSWHR award)

This project will evaluate novel blood proteins as potential risk markers for coronary heart 

disease and stroke in postmenopausal women, and will evaluate the extent to which changes in 

these biomarkers as a result of postmenopausal hormone therapy can help to explain the 

observed effects of postmenopausal estrogen and estrogen plus progestin on the risk for these 

major diseases. Confirmatory analyses of novel plasma protein associations with the risk of 

coronary heart disease and stroke will be carried out by applying enzyme-linked immunosorbent 

assays to baseline plasma specimens from cases and controls in the Women's Health Initiative 

postmenopausal hormone therapy trials. Candidate proteins were highly ranked in recent indepth proteomic discovery research. For CHD these are alpha-1-acid glycoprotein 1, 

thrombospondin 1, complement factor D preprotein, glutathione peroxidase 3, and insulin-like 

binding protein 1 (IGFBP1). For stroke the candidate biomarkers are IGFBP2, IGFBP6, insulinlike growth factor 2, hemopexin, and beta 2 microglobulin. Specimen analyses will be carried 

out for 349 CHD cases and for 1-1 matched controls, and for 326 stroke cases and matched 

controls. Data analyses will control for traditional cardiovascular disease risk factors, and for 

available biomarkers of inflammation, thrombosis, and lipids. Women developing CHD or stroke 

following their first year of hormone therapy trial enrollment, and their matched controls, will 

also have plasma concentrations assessed in 1-year blood specimens for the subset of these 

proteins found to be affected by estrogen-alone or by estrogen plus progestin in discovery work 

using the same proteomic platform. The baseline and 1-year protein concentrations will be 

jointly analyzed to assess the extent to which treatment-related changes in these protein 

concentrations can mediate hormone therapy effects on CHD and stroke. These analyses will 

incorporate a novel correction for biomarker measurement error. The project has a high 

probability of confirming some new biomarkers of CHD and stroke risk, and for providing 

additional insight into observed hormone therapy effects on these diseases. 
37

1-R21-HL-109822-01

Phytoestrogens, insulin resistance and endothelial function

Stachenfeld, Nina

Yale University School of Medicine

$ (NHLBI funded this ANSWHR award)

With the goal of reducing vasomotor symptoms and protection against the age-associated 

increase in cardiovascular disease risk, women are increasingly choosing over the counter 

phytoestrogens (such as genistein) in favor of estrogens prescribed by their physicians. Genistein 

may improve vascular function but not carry with it the increased breast cancer risks that have 

been associated with estrogen exposure. Insulin resistance increases cardiovascular disease risk, 

and may also interfere with the actions of genistein on cardiovascular function. Therefore, these 

studies have broad public health implications because it is important that women not have a false 

sense of cardiovascular protection while taking genistein. Genistein is the best studied and most 

common of the soy-derived phytoestrogens. Genistein is structurally similar to 172-estradiol and 

has high affinity for the ER2 receptor present in the human vasculature, but low affinity for the 

ER1 receptor present in reproductive organs. Studies support beneficial effects of soy-derived 

phytoestrogens on vascular reactivity and endothelial function. However, during genistein 

treatment the expected improvement in endothelial dependent dilation is attenuated in 

individuals with insulin resistance. This project is designed to study the impact of genistein on 

microvascular reactivity both in healthy women and in women with insulin resistance. Our 

general hypothesis is that genistein improves endothelial function through a nitric oxide 

mechanism in healthy women, but that this mechanism is ineffective in women with insulin 

resistance. We will use the cutaneous vasculature as a model to study endothelial function, and 

will infuse estradiol and genistein directly into the skin using microdialysis while measuring 

microvascular blood flow with laser Doppler flowmetry. Our first Aim will use dose-response 

curves to determine the 172-estradiol and genistein effects on the peripheral microvasculature in 

women with and without insulin resistance. We hypothesize that both hormone infusions will 

increase blood flow in both groups of women, but the vasodilation will be attenuated in women 

with insulin resistance. Our second Aim tests the hypothesis that nitric oxide mediates the 

estradiol and genistein-induced vasodilation in healthy women, but is not a factor in the more 

moderate vasodilation seen in women with insulin resistance. Women take genistein and other 

phytoestrogens assuming a level of cardiovascular protection, but data have not definitively 

demonstrated these benefits. Our studies will directly assess the extent to which genistein 

impacts vasodilation and examine the mechanism for its effects. Moreover, our findings will 

provide a basis to study the impact of genistein and other phytoestrogens on other conditions 

associated with compromised peripheral circulation such as Reynaud's disease and hypertension. 

The proposed studies will not only provide mechanistic information on the interaction between 

estradiol, genistein, insulin resistance and endothelial function, but will serve as a basis for future 

studies in older women and men with insulin resistance. 
38

CHRONIC FATIGUE SYNDROME

5-R01-AR-053821-05

HERV-K18 as a Risk Factor for CFIDS

Huber, Brigitte T. 

Tufts University Boston

$164, 058

The etiology of Chronic Fatigue Syndrome (CFS) is far from understood and is likely due to 

multiple genetic components. Infection with EBV and treatment with IFN-a have been 

implicated in the pathogenesis. Their laboratory has shown that EBV-infection, and exogenous 

IFN-a?, activate transcription of the env gene of a Human Endogenous Retrovirus, HERV-K18. 

This provirus is normally silent, but when induced it encodes a superantigen (SAg), which is a 

class of proteins that is capable of deregulating the immune system. Three alleles of HERV-K18 

env have been documented, K18.1, K18.2, K18.3, whose gene products have SAg activity, but 

are predicted to differ biochemically and functionally. Their working hypothesis is that HERVK18 is a risk factor for CFS. In a pilot study, the allele and genotype distributions of the HERVK18 env gene were compared between various groups of CFS patients and healthy controls. 

Although only a limited number of samples were available in the various cohorts, the odds ratios 

that were obtained were statistically significant. The most intriguing interpretation of these data 

are that they provide genetic evidence for the unique etiology of at least one group of CFS 

patients. Thus, it may be possible to delineate different subtypes of CFS, depending on the 

clinical history of the patients. It is now proposed to substantiate these pilot results, using a much 

larger cohort of 400 CFS patients associated with EBV that has been assembled by the coinvestigator, Dr. Renee Taylor. Dr. Ben Katz, board certified in both Pediatrics and Pediatric 

Infectious Diseases, will clinically evaluate the patient cohort, and Dr. Inga Peter, a genetic 

epidemiologist and biostatistician, will oversee the statistical analyses. In addition, the 

expression pattern of the HERV-K18 SAg during active disease versus intermission will be 

measured. Furthermore, T cell stimulatory activity of this SAg, expressed on peripheral blood 

lymphocytes of patients during the course of the disease, will be tested ex vivo, using a T cell 

hybridoma reporter assay that has been developed in their lab. Since SAg-activated T cells 

produce massive quantities of chemokines, lymphokines and neurokines, the expression of the 

HERV-K18 SAg could influence not only the immune system, but other organs as well. A 

positive association between CFS and either HERV-K18 alleles or expression patterns would 

open new avenues for the development of clinical treatments of this chronic disease. CFS is a 

disease that affects a significant number of people worldwide, yet the underlying mechanism(s) 

of pathogenesis remains unclear. The herpesvirus EBV and IFN-a have been suggested to be 

associated with CFS, although these concepts are far from accepted. They propose a novel 

genetic aspect in the EBV/ CFS association, namely the presence of certain HERV-K18 alleles 

that differ in their superantigen activity.
39

1-R21-NS-075653-01

Neuropathologic Abnormalities Define A Subgroup of Patients with CFS

Natelson, Benjamin 

Beth Israel Medical Center

$189,405

Chronic fatigue syndrome (CFS) is a medically unexplained debilitating disease that is diagnosed 

by the presence of a set of predefined symptoms. Because there are no validated diagnostic tests 

for the illness, progress in understanding its causes has been slow. From a series of studies by 

our group and others there has emerged strong preliminary evidence that supports the existence 

of a subgroup of CFS patients whose illness appears to be due to specific biological 

abnormalities in the brain. The purpose of this Exploratory/Developmental grant proposal is to 

conduct carefully controlled studies that will seek to confirm the existence of such a subgroup of 

CFS patients. If successfully completed, this study could validate an approach for selecting more 

homogeneous CFS patient populations in future research studies to enable them to focus better 

on understanding the exact cause of CFS and developing effective treatments for the illness. 

Chronic fatigue syndrome (CFS) is a debilitating multi-symptom disorder characterized by 

unexplained and prolonged fatigue, whose diagnosis is currently based on a relatively broad 

clinical case definition. Consequently, the pool of CFS patients included in clinical studies of the 

illness is greatly heterogeneous - a fact that might have impeded research progress to date. A 

major step forward in understanding the pathophysiology of CFS would involve reducing this 

heterogeneity by identifying one or more subgroups of patients with different pathophysiological 

causes of their illness, and then selecting one of these subgroups for inclusion into research 

studies. Over the past few years, we and others have provided substantial data supporting the 

existence of a subgroup of patients with a neurobiological cause for their illness, based on 

stratifying the sample according to the absence or presence of comorbid Axis I psychopathology 

(CFS-no psych or CFS-NP and CFS-psych or CFS-P, respectively). Compared to CFS-P 

patients, the CFS-NP patients had more cognitive dysfunction, a higher rate of abnormal 

cerebrospinal fluid (CSF) findings, lower regional cerebral blood flow (rCBF), and higher 

ventricular CSF lactate values. A further complication and limitation of these studies is that each 

had investigated only one brain-related variable, whose utility in separating CFS patients into 

subgroups was limited. The purpose of the present Exploratory/Developmental Research Grant 

(R21) proposal is to rigorously assess and confirm whether patients in the CFS- NP group have 

consistent abnormalities across several different neuropathological variables - an outcome that 

would be expected if this group, in fact, does have distinct neurobiological underpinnings. 

Specifically, in the same subjects, we will (a) assess cognitive function using objective 

neuropsychological testing; (b) conduct biochemical analysis of spinal fluid samples obtained by 

lumbar puncture; and (c) measure rCBF and ventricular lactate using magnetic resonance 

imaging and spectroscopy, respectively, in CFS-P and CFS-NP patients. This will allow us to 

test the hypothesis that CFS-NP patients have more abnormalities in these outcome variables 

than CFS-P patients. Our second Aim will use the results from the first Aim in a cluster analysis 

to attempt objective, data-driven classification of the CFS subjects into subtypes, and then 

compare the resulting subgroups based on membership into CFS-NP or CFS-P groups. This aim 

will test the hypothesis that the results of the cluster analysis will identify a group with 
40

abnormalities across the multiple brain-based variables studied, and this group will be 

constituted of significantly more CFS-NP patients than in other groups.

CRANIOFACIAL

N01-DE32636-23-0-1 

International Research Registry Network for Sjogren’s Syndrome

Shiboski, Caroline 

University of California San Francisco

$150,000

The purpose of this contract is to develop an International Research Registry Network for 

Sjogren’s Syndrome. Specific aims are: 1. To develop standardized diagnostic criteria for 

Sjogren’s Syndrome (SS) through a prospective cohort study design and based on analysis of 

existing criteria and their current usage; adoption of a new objective "working standard" (in lieu 

of a "gold standard"); and measurements of the sensitivity, specificity and accuracy of many 

combinations of diagnostic tests based on that standard. 2. To collect, process and store clinical 

data and biospecimens from patients diagnosed using these new criteria and controls. 3. To 

develop a data and biospecimen bank. 

DIABETES

5-U01-DK-057136-13

Look AHEAD: Action for Health in Diabetes

Espeland, Mark

Wake Forest University Health Sciences

$100,000

Look AHEAD is randomized clinical trial examining the long-term health effects of an intensive 

weight loss intervention in approximately 5,145 overweight volunteers with type 2 diabetes. 

Participants are randomized to an intensive lifestyle intervention designed to achieve and 

maintain weight loss by decreased caloric intake and increased physical activity, or to a control 

program of diabetes support and education. The primary outcome of Look AHEAD is the 

aggregate occurrence of severe cardiovascular events (fatal and non-fatal Ml and stroke and 

cardiovascular deaths) over a planed follow-up of 11.5 years. The original grant application 

provided funding for the first 7 years of the study (1 year for study design and 6 for execution of 

the trial). The present grant application is for an additional 7 years of funding to complete the 

Look AHEAD trial. All aspects of the study have proceeded extremely well - the sample of 

5,145 was recruited on time; retention has been excellent and the intervention has been effective 

in producing initial weight loss and maintaining it over time. All 16 clinical sites have been 

successful in recruitment, retention, and delivery of the intervention and the DSMB has been 
41

very positive about the execution of the trial. The present application reviews the overall design 

of Look AHEAD, progress to date, and plans for the future. Specific Aims are to retain the 

cohort over time, continue to complete annual in-person visits and semi-annual telephone 

interviews for outcome assessments and continue to administer the lifestyle intervention. These 

procedures will enable us to analyze the effects of the intervention on serious cardiovascularrelated factors and complications, and cost-effectiveness of the intervention.

5-U01-DK-048489-18

Diabetes Prevention Program Outcomes Study

Fowler, Sarah E.

George Washington University

$900,000

The Diabetes Prevention Program is a multicenter controlled clinical trial examining the efficacy 

of an intensive life-style intervention or metformin to prevent or delay the development of 

diabetes in a population selected to be at high risk due to the presence of impaired glucose 

tolerance (IGT). Development of diabetes, defined by 1997 ADA criteria, is the primary outcome 

while cardiovascular disease and its risk factors are important secondary outcomes. The DPP 

began recruitment in mid-1996. At the time of this application, total study exposure is a mean of 

approximately 3 years (range 2 to 5) with a total of approximately 10,000 patient years in the 

3,234 volunteers in the 3-arm study. On the basis of a statistically significant and clinically 

compelling decrease in the development of diabetes in the life-style intervention and metformintreated groups (58% and 31% reductions, respectively) compared with the placebo treated group, 

the DPP Data Monitoring Board and NIDDK ended the masked treatment phase of the study in 

May, 2001, one year earlier than originally planned. This application is designed to take further 

advantage of the scientifically and clinically valuable cohort of DPP volunteers and the large 

volume of data collected during the study. The highly compliant DPP cohort, including 45% 

minorities, is the largest IGT population ever studied. Moreover, the sub-cohort that has 

developed diabetes (n approximately 700) has been followed from near the exact time of diabetes 

onset. Clinically important research questions remain in the wake of the DPP. The carefully 

collected, centrally measured and graded data in this cohort should help to answer, definitively, a 

number of important questions regarding the clinical course of IGT and early onset type 2 

diabetes. Specific aims include: 1. Examine the long-term effects and durability of prior DPP 

intervention on the major DPP outcomes including diabetes, clinical cardiovascular disease, 

atherosclerosis, CVD risk factors, quality of life and cost-benefit; 2. Determine the clinical 

course of new onset type 2 diabetes and IGT, in particular regarding micro-vascular and 

neurologic complications; 3. Determine the incidence of cardiovascular disease (CVD), CVD 

risk factors and atherosclerosis in new onset type 2 diabetes and IGT; and 4. Examine topics 1-3 

in minority populations, men vs. women, and in older subjects in the DPP. 
42

DIETARY SUPPLEMENTS/ CAM

5-R21-AT-005377-02

Identification of novel phytoprogestins from hops and red clover

Burdette, Joanna E

University of Illinois at Chicago 

$194,287

Women are already taking phytoestrogens in botanical extracts for menopausal symptoms, and 

the incorporation of progestins may prevent hyperplasia and cancer of the uterus. As women 

search for more potent alternative estrogens to satisfy the need for menopausal symptom 

alleviation, the chance for hyperplasia in the uterus increases and makes the characterization of 

novel phytoprogestins crucial. Hormone replacement therapy (HRT) is the most commonly 

prescribed medication for the alleviation of menopausal symptoms. Unopposed estrogen 

replacement therapy increases the risk of developing endometrial cancer by 120% for every 5 

years of use. To eliminate this risk in women with a uterus, the addition of progesterone to HRT 

in the form of combined estrogen/progesterone replacement has been implemented. Considerable 

evidence now indicates that the addition of synthetic progestins to HRT increases the risk of 

breast cancer as well as many other deleterious side effects. In response to the problems 

associated with HRT, millions of women are exploring the use of botanicals and dietary 

supplements for the alleviation of climacteric symptoms. However, the use of botanicals with 

only plant-derived estrogens in the absence of progestins might increase the risk for developing 

endometrial cancer similar to estrogen alone. Two common supplements, hops and red clover, 

contain phytoestrogens that bind and activate estrogen receptors. Interestingly, when hops and 

red clover are given orally to ovariectomized rats, uterine weights are not significantly increased 

in animals treated with a crude extract but are significantly increased in animals given an 

equivalent dose of the pure phytoestrogen. The hypothesis of this grant proposal is that selective 

natural progesterone compounds can be identified from botanical extracts to generate a combined 

phytoestrogen-phytoprogestin alternative to traditional hormone replacement therapy. The 

presence of both estrogen and progesterone receptor agonists in one botanical extract may 

provide both the benefits of estrogens for alleviation of menopausal symptoms and the 

progesterone necessary to combat formation of uterine cancers. Selective and safer progestins 

might also be identified from botanical sources improving the overall behavior of the progestin 

used in HRT. In order to provide support for this hypothesis the following specific aims are 

proposed: Aim 1. Do botanical extracts contain phytoprogestins and what are the pure 

compounds responsible for the progesterone-like activity? Aim 2. Are phytoprogestins specific 

and selective for uterine progesterone receptors? Aim 3. Are phytoprogestins protective against 

uterine hyperplasia in an ovariectomized rat model? These studies will provide a clear 

justification for the use of botanicals that have the possibility of providing both estrogen and 

progestin-like activity but with more selective and safer profiles for the treatment of menopausal 

symptoms. Women are already taking phytoestrogens for menopausal symptoms, and 

incorporation of progestins may prevent hyperplasia and cancer of the uterus. 
43

GENITOURINARY

5-U01-DK058229-11

Urinary Incontinence Treatment Network

Tennstedt, Sharon L 

New England Research Institutes, Inc

$100,000

This proposal is submitted in response to RFA-DK-06-501 for continuation of the Urinary 

Incontinence Treatment Network (UITN) Data Coordinating Center (DCC) at New England 

Research Institutes, Inc. The DCC is responsible for the scientific management of the studies, 

including directing, training, and monitoring the performance of Clinical Centers in enrollment, 

data collection, and data management as well as for all data analysis, and reports to the DSMB. 

In Phase I and continuing to Phase II, NERI has provided several unique and innovative tools 

and capabilities, including a proprietary Web-based data management system, an automated 

patient randomization system, and an electronic repository for UDS tracings. The DCC is also 

responsible for network communications and meeting support and provides a secure study 

website and a public website. DCC scientists play a leadership role in all network activities, 

including protocol development, standing committees and work groups, manuscript development 

and presentations. Phase II will focus on conduct of the TOMUS trial as well as continuation of 

the observational follow-up studies for the SISTEr and BE-DRI studies (i.e., E-SISTEr and EBE-DRI) of Phase I. Primary Aims of TOMUS are to compare objective and subjective cure 

rates for stress incontinence at 12 and 24 months between the retropubic and transobturator 

midurethral sling procedures. Performance of these procedures is increasing rapidly with limited 

data available on safety and efficacy. Therefore, this study will compare the efficacy and safety 

of the retropubic and transobturator (inside-out and outside-in) procedures in a 2-arm RCT; 588 

women with stress Ul will be enrolled. Primary Aim of E-SISTEr is to compare long-term (60 

mos.) effectiveness and durability of the Burch colposuspension and autologous fascial sling for 

treatment of stress Ul in a randomized cohort of 655 women. Primary Aim of E-BE-DRI is to 

examine long-term (26 mos.) durability of the addition of behavioral treatment to drug therapy 

for treatment of urge Ul in a randomized cohort of 307 women. The UITN is a multidisciplinary, multi-center group of Investigators dedicated to high impact clinical research 

regarding the prevention, evaluation and management of Ul to improve the quality of life for 

adults. The UITN is conducting 3 studies of treatments for both stress and urge urinary 

incontinence.
44

1-R21-HD-069962-01

Tailored Outcomes for Female Urinary Incontinence

Sung, Vivian W

Women & Infants Hospital, Providence RI

$ (NICHD funded this ANSWHR award)

With the aging population, the number of women seeking care for urinary incontinence (UI) will 

increase. High- quality, patient-important outcomes that can be tailored, are efficient and monitor 

treatment outcomes from the patient perspective are critical to improving scientific knowledge 

and the care of women who suffer from UI. Urinary incontinence (UI) disproportionately affects 

women over men and is associated with embarrassment, social and functional decline. 

Treatments are primarily aimed at improving aspects of a woman's quality of life and function; 

therefore, high quality patient-reported outcomes (PRO) that cover multiple dimensions are 

paramount to inform treatment progress. Limitations of existing UI PRO measures include their 

inflexibility, significant respondent burden, and inability to be personalized. The overarching 

goal of this proposal is to make a major advance in UI PRO measures by developing an 

innovative measurement system that is multi- dimensional, flexible, and efficient, can be tailored 

to individuals, yet also decreases respondent burden. Such a system is likely to be accepted by 

patients, clinicians, researchers, and industry for evaluating treatment outcomes from the patient 

perspective and can streamline research findings and patient care. Using item response theory 

and computerized adaptive testing, The NIH Patient-Reported Outcomes Measurement 

Information System (PROMIS) has developed core PRO item banks relevant to a wide range of 

chronic diseases. As comprehensive as PROMIS is, it does not fully address the needs of women 

with UI. To fill this need, we will build on our previous work to continue validation and 

calibration of UI-specific item banks based on an expanded PROMIS conceptual framework that 

is sensitive to the outcomes valued by women with UI. Specifically, our aims are to: 1) confirm 

face and content validity of our UI item banks and conceptual framework through cognitivebased interviews and expert review; 2) calibrate and field-test the item banks using item response 

theory in 700 women with UI recruited across two hospital settings; and 3) develop and pilot-test 

a web-based UI-computerized adaptive test prototype (UI-CAT). We will evaluate 

item/model/person fit, compare item discrimination power, and assess differential item 

functioning across demographic variables, UI severity and type, and co-existing pelvic floor 

disorders. We have convened an interdisciplinary team of experts in female UI, PRO 

development, PROMIS methodology, item response theory, computerized adaptive testing, and 

informatics. The application of modern psychometrics and computerized adaptive technology 

can dramatically improve our PRO measurement capabilities in female UI and women's health. 

The UI-CAT can be used to help tailor our treatments to the needs and values of women with UI, 

improve the specificity of our treatments, and improve the delivery of personalized care to 

women. 
45

1-R24-DK-094575-01

Microbiomes of Interstitial Cystitis

Schaeffer, Anthony J

Northwestern University

$50,000

Interstitial cystitis/painful bladder syndrome (IC) is a debilitating chronic bladder condition 

without known cause or effective treatments. This study will develop an interdisciplinary team to 

explore the novel question of whether alterations in the large bacterial communities that populate 

the gastrointestinal and reproductive tracts play a causal role in IC. Interstitial cystitis/painful 

bladder syndrome (IC) is a devastating condition characterized by severe pelvic pain and voiding 

dysfunction. Despite years of investigation, no etiology or widely effective therapies exist for IC, 

indicating the needto consider new ideas and approaches. Based on several lines of evidence, the 

"microbiome" is an emerging field of study that has the potential to play a significant role in our 

understanding of I. First, many IC patients exhibit Gl or reproductive tract co-morbidities. 

Second, it is established that crosstalk exists among the bladder, Gl tract, and reproductive tract. 

Third, we find that bacteria can mediate a range of pelvic pain responses, from pain suppression 

to causing chronic pain. Fourth, microbial flora densely populate certain body sites, indeed 

outnumbering human cells, and new findings demonstrate that altered microbiomes can drive 

complex diseases. We therefore will develop an interdisciplinary team to address this novel 

question: is an altered gastrointestinal and/or reproductive tract microbiome associated with IC? 

Our team will bring together clinical expertise in IC, methodologic and biologic expertise in 

defining microbiomes of the Gl and reproductive tracts, and expertise in the microbial basis of 

pelvic pain. Our team will exploit the synergies from these key fields to develop specific 

hypotheses and strategies for defining associations between microbiomes and IC. Moreover, 

clinically relevant murine models will be developed to establish a causal link between altered 

microbiomes and modulation of pelvic pain. Defining IC microbiomes has potentially major 

significance for understanding IC etiology, mechanisms, and treatments. IC patients often have a 

history of antibiotic treatments for urinary tract infection, yet antibiotics can shift microbial 

diversity and thereby cause disease. Altered IC microbiomes could result in dysfunctional 

modulation of pelvic pain via organ crosstalk or expanded reservoirs of uropathogens. Finally, 

manipulation of microbiomes is proving efficacious in other clinical specialties, suggesting the 

possibility of possibility of convenient probiotic therapies for IC. 

1-R24-DK-094583-01

Sensory Sensitivity and Urinary Symptoms in the Female Population

Clemens, J. Quentin

University Of Michigan

$50,000

Bladder symptoms such as pain and urgency are very common, and treatments are poorly 

effective. These studies will examine for clinical evidence of global pain hypersensitivity in 

these patients. If a global pain abnormality is identified, additioal studies can be done to examine 

the etiology of these symptoms and design novel treatments that are focused on central, rather 

than peripheral, pathophysiology. Bladder pain and discomfort, as well as urinary urgency and 
46

frequency, are common and bothersome symptoms seen in the general population. Clinical 

diagnostic terms used to describe these symptoms include interstitial cystitis (IC), painful 

bladder syndrome (PBS), chronic prostatitis, and overactive bladder (OAB), but there is 

tremendous overlap between these entities, and the distinction between them is based more on 

imminence than evidence. Pain and/or sensory sensitivity have been suspected to play a role in 

the pathogenesis of both bladder pain and urinary urgency/frequency. However, there has never 

been a study to determine whether entities such as IC/PBS and OAB might merely represent 

different points in a continuum of bladder sensory sensitivity. Moreover, we know of no studies 

that have directly compared whether sensory sensitivity in the bladder is related to global (i.e. 

CNS-mediated) sensory sensitivity. In the proposed study, a team of investigators with 

complementary expertise will perform a population-based study assessing bladder and overall 

sensory sensitivity, in a cohort of women chosen to be representative of the general population 

with respect to the entire continuum of bladder pain (from none to severe), and symptoms of 

urgency/frequency. These individuals will undergo urodynamics to measure sensory sensitivity 

in the bladder, as well as pressure pain and auditory loudness thresholds. Our Specific Aims are 

to demonstrate that in the population, 1) sensory sensitivity in the bladder is related to sensory 

sensitivity elsewhere in the body, suggesting that this is a CNS-driven mechanism, and 2) those 

individuals in the population that have more pronounced global sensory sensitivity will display: 

a) more bladder pain, b) more urgency/frequency, and c) more other symptoms of centrallymediated pain states, such as pain elsewhere, fatigue, and insomnia. We feel that these studies 

are crucial to better understand the relationship between sensory sensitivity and urinary

symptoms, and to add to the evidence necessary to appropriately diagnose and treat these 

symptoms and individuals. 

GLOBAL HEALTH

3-D43-TW-008438-03S2

QUIPU: The Andrean Global Health Informatics Research and Training Center

Garcia, Patricia Jannet

Universidad Peruana Cayetano Heredia, Lima, Peru

$10,000

Within South America, the Andean Region (AR) is the most disadvantaged. However, modern 

technology such as computers, cellular phones, and other information and communications 

technologies (ICT) are becoming more widely available in the region. The fields of informatics 

and global public health are both growing, but we lack an institutionalized effort to train 

professionals to apply ICT to global health issues in the context of regional needs and to develop 

health information technology experts capable of linking informatics with health research. The 

overarching goal of this proposal is to establish the "QUIPU: Andean Global Health Informatics 

Research and Training Center," a center of excellence for training and research in global health 

informatics (GHI) to serve as a hub for addressing the national and regional needs for highquality training in the Andean Region (AR) at a fraction of the cost of similar training programs 
47

in the U.S. The specific aims of the proposal are: 1. To develop and implement short-term and 

long-term training opportunities in GHI within the AR; 2. To engage emerging investigators in 

regionally pertinent research in health informatics and bioinformatics; and 3. To expand and 

consolidate a research network to link researchers in the AR, promoting south^south 

collaborations, as well as with colleagues from partner universities in the U.S. and other 

institutions. The Center will expand from the Universidad Peruana Cayetano Heredia (UPCH) 

and the U.S. Naval Medical Research Center Detachment (NMRCD) in Lima, Peru, two 

universities from the AR, the Universidad del Cauca (UCA) in Colombia and the Universidad 

Andina Simon Bolivar (UASB) in Ecuador, and the University of Washington (UW); who will 

work together as a Consortium to collaboratively implement QUIPU. The proposed program 

builds on existing and emerging collaborations between the four institutions, as well as a longstanding training-centered collaboration between UPCH and UW through NIH-Fogarty funded 

programs which allowed the development of a critical mass of trained researchers at UPCH and 

in Peru. We envision GHI as an umbrella for integrating health informatics and bioinformatics 

into clinical, biomedical and behavioral research issues that are key to advancing the health of 

populations in the AR and around the globe. The proposed program includes training and a 

research component. The training component will offer courses, two Certificate programs (health 

informatics and bioinformatics), as well as Masters and PhD programs for advanced students. 

We plan to offer 12 scholarships for short courses, 11 for Certificates, 14 for Masters and 2 for 

PhD degrees during the 5-year grant. Candidates will be selected from Andean countries with a 

focus on Colombia, Ecuador and Peru. Video conferences and internet-based courses will be 

used to expand availability to a broader pool of students. The component for research in health 

informatics will strengthen NIH and non-NIH funded research conducted in the region, by 

providing competitive research awards, opportunities within already established research 

projects, and links to other researchers within the networks of collaborating institutions, 

including a regional research conference. 

3-R01-HD-061115-03S1

Gender Equity-Focused, Male-Centered Family Planning for Rural India

Saggurti, Niranjan

Boston University

$60,573

The major barrier to India meeting its national goal of replacement fertility is the huge 

discrepancy between urban and rural family planning, with rural young women at highest risk for 

unplanned and unspaced pregnancies. These concerns are considered to drive the persistent and 

unacceptably high rates of maternal and infant mortality in India. Major impediments to these 

young wives' acquisition of family planning services include high male partner control over 

reproductive decision-making, low mobility, and very low access to family planning services in 

villages. Such findings document the need for male-centered family planning efforts available at 

the village level, to better meet the needs of rural young wives. These male-centered efforts must 

address male gender role and gender inequity ideologies and norms (e.g., son preference, wife 

abuse) and marital communication, as these factors are associated with lower likelihood of 

contraceptive use in rural young Indian couples. Hence, the proposed study involves 

development and testing of the CHARM Program, a gender equity (GE)-focused, male-centered 
48

family planning (FP) program delivered by private village health providers (VHPs), via a publicprivate partnership with primary health centers (PHCs) serving rural India. In Phase 1 we will 

conduct formative research including health care resource mapping of Vasai within the Thane 

district of Maharashtra to identify villages and VHPs for inclusion in subsequent research and 

intervention. We will also conduct in-depth interviews with rural young husbands (n=30), rural 

young wives (n=20), and health care providers (n=12), as well as focus groups with mothers' of 

rural young husbands (n=40). These data will be used to develop the CHARM program and 

efficacy trial. Phase 2 will involve development and pilot testing of CHARM protocols and 

training of VHPs for their role in the intervention trial (Phase 3). The CHARM intervention will 

involve VHP-delivered GE and FP counseling and services, delivered over 3 intervention 

sessions + 2 booster sessions. Phase 3 will involve evaluation of CHARM, using a two-armed 

randomized controlled trial design. Villages (N=50) will be randomized to receive either 

CHARM or the control program (standard FP referral to government public health centers 

[PHCs] located outside of villages), to assess treatment impact on spacing contraceptive use, 

pregnancy, and unmet family planning need. Intervention effects will be assessed via behavioral 

surveys collected on hand-held computers (PDAs) with rural young husbands (18-30 years) and 

their wives (N=1500 couples, 30 couples per village) at baseline and 6,12, and 18 month followup, as well as pregnancy tests from wives, conducted at baseline and 18 month follow-up. A 

process evaluation will be undertaken via interviews with study participants and VHPs, as well 

as through VHP observations and clinical record review, to assess program adherence, 

participation rates, response to program, and ease of delivery. In-depth interviews will also be 

conducted with key informants from the village and public and rural health systems to assess 

sustainability and institutionalization of the model.

3-D43-HD-065249-03S1

Interdisciplinary Research Training: NCD Epidemiology And Prevention In India

Tandon, Nikhil

Centre For Chronic Disease Control, New Delhi, India

$50,240

NCDs are a large, growing, and costly problem for India. Over the next decade, the country is 

projected to lose $237 billion in national income due to heart disease, stroke, and diabetes, and to 

account for 40-60% of the global CVD burden. Despite these projections, research infrastructure 

is lacking, and building research capacity at post-doctoral and junior faculty levels is clearly 

identified as a priority by the Government of India and health organizations. There is an acute 

shortage of post-doctoral and junior faculty research capacity in India, with no postdoctoral 

programs in epidemiology and prevention of non-communicable diseases (NCDs). The proposed 

interdisciplinary training program will focus on the epidemiology and prevention of NCD across 

the life-course, in cross-connecting subject areas (child health; nutrition and lifestyle, 

environmental health, obesity and diabetes, stroke and other vascular diseases) and population 

science disciplines (epidemiology and biostatistics; clinical trials; translation research, social 

sciences, and economics). This effort will leverage an established network of research 

collaborations involving partners in India and the US (Ovations Center for Excellence in Chronic 

Diseases, New Delhi). The program will have two components: (1) Short-term training in year 1: 

Eight junior faculty researchers will receive four months of training at Emory to acquire specific 
49

and focused mentoring and research skills. (2) Long-term training in years 2-5: A total of ten 

post-doctoral fellows (one batch of five in years 2-3 and one batch in years 4-5) will receive 24 

months of training (four months at Emory in the first year, six weeks at Emory in the second 

year, and the remaining 18.5 months in India). Training components include mentored research, 

coursework, professional development (ethics, grants-writing, communication skills), and an 

emphasis on context-specific innovation in health programs and research. Collaboration with 

Emory will compliment India-based mentoring and training, and permit transfer of skills and 

expertise in specific areas. The program will build a critical mass of NCD researchers and 

incorporate them within integrated NCD research programs in India. An important innovation of 

our program is the emphasis on retaining talented young scientists in India, enabling them to 

develop world-class research skills in an Indian-based training program, facilitating international 

collaborations, and providing end-of-training grants to promote in-country research projects. We 

expect the program to have a cascade effect, as each of the 18 trainees will serve as a resource 

upon completion of the program, disseminating knowledge and skills to other researchers at incountry institutions. 

3-D43-TW-008652-02S1

Training Program on Operational and Health Services Research for Malaria in Mali

Doumbia, Seydou

Johns Hopkins University

$45,172

Lack of sound operational research to accompany past efforts to implement large-scale malaria 

control programs has been cited as one reason for their ultimate failure. Mali is particularly in 

need of such a training program because it is a challenging environment for implementation of 

malaria interventions (low population densities, low literacy), and there are few researchers 

trained in operational research in Mali. The training program's main aim will be to strengthen 

current malaria prevention and control efforts in Mali by providing training in Mali in relevant 

research and evaluation skills. A secondary aim will be to support public health graduate training 

in Mali at both the masters and doctoral levels. Each year during the first three years of the 

training program, two trainers will spend two months at the JHSPH, take two or three courses, 

and develop the detailed training curriculum for a course they will offer upon their return to 

Mali. One 5 to 10 day course on malaria prevention and control will be organized each year for 

approximately 25 participants. Participants will be drawn from Ministry of Health personnel and 

personnel working in control projects implemented by UNICEF, NGOs or other organizations. 

The Department of Public Health of the University of Bamako is initiating a 2-year Masters in 

Public Health Program during the 2009-2010 academic years. This training grant will support a 

first cohort of 5 students then 3 subsequent cohorts of 3 students per year. On-going 

collaboration with the Malaria Research and Training Center provides opportunities for students 

to be exposed to malaria research, and to carry out their field placements at MRTC field sites and 

laboratories. Two students will be supported to carry out doctoral studies at DPH during Years 3 

to 5 of the training grants. Students will be recruited from among the first 5 students to complete 

the MPH, and students with MPH from other universities. During the fourth and fifth years of the 

training grant, the students will spend one term each year at JHSPH taking additional courses not 

offered at DPH and getting input from JHSPH faculty on their dissertation research. 
50

3-D43-TW-009101-01S1

China-Rochester Suicide Research Training Program (CRSRT)

Caine, Eric D

University of Rochester

$10,000

This D43 NCD-LIFESPAN application is entitled the China-Rochester Suicide Research 

Training Program (CRSRT). It is built upon the International Clinical, Operational and Health 

Services Research Training Award ("ICOHRTA") program that has been funded since 2001 

(D43TW005814). The current proposal is written in response to PAR-10-257 for a Chronic, 

Non-Communicable Diseases and Disorders Across the Lifespan: Fogarty International Research 

Training Award (NCD-LIFESPAN). Suicide is a major public health problem in China. It is the 

fifth leading cause of death overall, and the leading cause of death for individuals in the 15- 34 

year old age range. It has a national rate of approximately 23 deaths per 100,000; during 1995-

1999, approximately 287,000 died by suicide. In response, we now are systematically growing 

the CRSRT to encompass multiple complementary settings that serve to diversify the academic 

breath and geographical distribution of our initiatives, increase our committed mentors, and 

widen the pool of applicants. Our high rate of positive outcomes during the past decade 

reinforces the rewarding nature of our high-intensity mentoring strategy. The CRSRT involves 

the Center for the Study and Prevention of Suicide (CSPS) of the University of Rochester 

Medical Center (URMC), and six key collaborators in China who bring a diversity of skills and 

leadership to our growing collaborative efforts, with centers in Beijing, Shanghai, Chengdu, and 

Changsha. Our proposal reflects an ongoing, self-scrutinizing process that has informed our 

efforts to: 1) build training and research infrastructure, focusing primarily on public health and 

population-oriented research and prevention efforts; 2) identify and train excellent future 

scientists; and 3) develop new research findings that will inform efforts to prevent suicide in 

China during the coming decades. The CRSRT involves a year of intensive training in the CSPS, 

followed by two further years of mentored research in China. We provide trainees with the skills 

to emerge as independent investigators through intensive one-to-one mentoring and engagement 

in a variety of peer-oriented training experiences. We will continue to systematically evaluate the 

effectiveness of our recruiting, training, and research efforts.

5-R01-AI-083563-02

Congenital Transmission of Lineages I and II of Trypanasoma cruzi

Buekens, Pierre

Tulane University

$10,000

A better understanding of the epidemiology of Trypanasoma cruzi (TcI) congenital infection is a 

crucial step toward the potential development of screening and early treatment programs in 

Mexico and Central America, as well as in the United States, where large immigrant populations 

come from countries where TcI predominates. Thus, the proposed research project is highly 

relevant to public health. T. cruzi has been divided into two main lineages: T. cruzi I (TcI) and 

T. cruzi II (TcII). TcI is predominant in Mexico and Central America, while TcII is predominant 
51

in most of South America, including Argentina. In recent studies from Argentina, the risk of 

congenital transmission has been estimated to vary between 2.6 percent and 7.9 percent. By 

contrast, we know very little about the congenital transmission of TcI. It has been suggested that 

congenital transmission of T. cruzi is strain related, and there is an urgent need to know if TcI 

transmits differently than TcII. Our primary hypothesis is that congenital transmission rates are 

different for TcI versus TcII. Our secondary hypothesis is that the characteristics of T. cruzi 

infected mothers (e.g., age, parity, transmission in previous pregnancies) and their exposure to 

vectors are different in regions where TcI is predominant versus regions where TcII is 

predominant. To test these hypotheses, we propose to conduct a prospective study to enroll at 

delivery 10,000 women in Mexico, 5,000 women in Honduras, and 5,000 women in Argentina. 

We will measure transmitted maternal T. cruzi antibodies in cord blood, and, if the results are 

positive, we will identify infants who are congenitally infected by performing parasitological 

examinations on cord blood and at 4-8 weeks, and serological follow-up at 10 months. We will 

also perform standard PCR, real-time quantitative PCR, and T. cruzi genotyping on maternal 

blood, standard PCR and T. cruzi genotyping on the cord blood of congenitally infected 

newborns, and serological examinations on siblings. We will estimate the exposure to vectors in 

the household. In addition, we will measure prenatal outcomes among infected and uninfected 

infants with seropositive mothers, and the birth weight of their siblings. The specific aims of this 

study are: 1) To determine the rate of congenital transmission of TcI compared to TcII; 2) To 

compare the T. cruzi infected mothers' characteristics and exposure to vectors in regions where 

TcI is predominant and regions where TcII is predominant; and 3) To describe the birth 

outcomes of infected and uninfected infants born to TcI and TcII seropositive women. 

3-R01-HD-041455-06S1

India Human Development Survey

Desai, Sonalde B.

University of Maryland

$42,600

As Indian economy grows, health profile of the Indian society is changing along with the 

mechanisms for financing health care. The proposed study will collect data that will facilitate 

research on a variety of topics associated with public health and child development in India. Data 

from India Human Development Survey I and II will be premier public resource for all 

researchers. Researchers from the University of Maryland, the National Council of Applied 

Economic Research, and AMS Consulting, together with an interdisciplinary team of 

collaborators, propose to field the second round of the India Human Development Survey 

(IHDS-II), a nationally representative survey of 41,554 households who were surveyed in 2004-

2005 under NIH grants R01HD041455 and R01HD046166. This survey is designed to be a 

premiere public resource for researchers interested in studying different dimensions of human 

development in India. The proposed project has two specific aims: A. Resurvey the households 

initially surveyed in 2004-5 once again in 2011-12. Given the vast changes in India since 2005, 

IHDS-II will provide a multi-topic, multi-purpose source of data for international and Indian 

research on health, education, income, employment, gender and social inequality. Panel data will 

allow an exploration of lagged effects as well as better estimation of causal relationships. IHDSII will permit the analysis of two major government programs initiated since 2005 - the National 
52

Rural Employment Guarantee Scheme and the National Rural (and now Urban) Health Mission. 

These programs introduce exogenous changes in the male/female wage gap and provide cash 

incentives for hospital deliveries. Panel analyses of these changes create new opportunities to 

investigate the determinants of gender gaps in employment, education, and health. B. Expand the 

range of data collected. Data collection will be expanded in two principal ways: 7 Some 

questions from IHDS-I will be revised and extended based on our field experience, analysis 

results, and user feedback. 7 New modules will be added to study the mechanisms through which 

spatial disparities in health and education emerge. Research conducted under the parent grant has 

highlighted the importance of spatial disparities in health, education, income, and employment as 

well as caste and gender differences in these outcomes. Analyses of IHDS-I have showed us that 

these large regional differences persist in spite of a wide range of controls for individual level 

factors. In this renewal, we seek to measure a broader range of mechanisms through which these 

spatial disparities emerge. New efforts focus on supplementing the household surveys with 

expanded geographic data and institutional surveys. 

3-R21-HD-062821-02S1

Empowering Daughters and Mother-in-laws to Mitigate Gender-based Violence and 

Promote Women's Health in India

Krishnan, Suneeta

Research Triangle Institute, Research Triangle, NC

$50,438

A growing body of research indicates that gender-based violence (GBV) is a major global public 

health challenge. Yet, there is a dearth of evidence to guide program planning and policy-making 

efforts to reduce GBV. Our study will evaluate the feasibility, safety, and potential effectiveness 

of an innovative women's empowerment intervention to reduce GBV and related adverse health 

outcomes. It is expected that the study findings will provide evidence to determine if a phase 3 

effectiveness trial is merited and advance the science underlying GBV prevention. A growing 

body of research indicates that gender-based violence (GBV) is a major global public health 

challenge. Yet, there is a dearth of evidence to guide program planning and policy-making 

efforts to reduce GBV. Our study will evaluate the feasibility, safety, and potential effectiveness 

of an innovative women's empowerment intervention to reduce GBV and related adverse health 

outcomes. It is expected that the study findings will provide evidence to determine if a phase 3 

effectiveness trial is merited and advance the science underlying GBV prevention. The 

prevalence of physical, psychological, and sexual gender-based violence (GBV) is staggeringly 

high among young, married women in India. However, few GBV prevention interventions have 

been implemented, and none of these interventions has been rigorously evaluated. We aim to fill 

this gap by conducting exploratory research on an innovative women's empowerment-based 

GBV prevention intervention. The proposed study builds on our previous research in urban poor 

communities in Bangalore, India, which revealed that efforts to enhance young, married women's 

power and to mitigate GBV will be limited if the broader context of their lives, which is shaped 

mainly by the marital family, is unaddressed. Previous research suggests that mothers-in-law 

(MILs) are a strategic familial entry point and that it may be possible to redirect the power they 

wield in the family toward reducing GBV against daughters-in-law (DILs). Based on this 
53

evidence and women's empowerment approaches that have successfully reduced GBV 

elsewhere, we developed the intervention Dil Mil (meaning "Hearts Together" in India's national 

language, Hindi). Guided by the Social Cognitive Theory and Heise's social-ecological 

framework of GBV, Dil Mil aims to empower DIL-MIL dyads with knowledge, skills, and social 

support critical to the mitigation of GBV and related adverse health outcomes among DILs. We 

chose antenatal care as the context for implementing this intervention because of women's nearly 

universal use of antenatal care in urban India. A phase 1 pilot study demonstrated that our 

approach is acceptable and likely to be safe. The aim of this R21 is to conduct a phase 2 trial to 

examine the feasibility, safety, and potential effectiveness of Dil Mil in order to determine if a 

phase 3 effectiveness trial is merited. The proposed study is a randomized controlled trial with 

140 dyads comprising pregnant DILs (aged 18 to 30 years, in their first or second trimester of 

pregnancy, with a history of GBV) and their MILs. Recruitment will take place at four primary 

health centers serving poor communities in Bangalore. Dyads will be offered standard care or 

standard care plus the Dil Mil intervention, and evaluations will be conducted at 3 months and 6 

months postpartum. We will characterize the study population using descriptive statistics and 

assess feasibility and safety of the intervention using qualitative and quantitative data (Aim 1). 

Data on the effect of the intervention on intermediary outcomes-the empowerment of DILs and 

MILs (Aim 2)-and on the incidence of GBV among DILs during the first 6 months postpartum, 

DILs' perceived quality of life and psychosocial status, and maternal and infant health outcomes 

(Aim 3) will be analyzed using the intention-to-treat principle. Based on this evidence, we will 

determine if a phase 3 trial is merited. In conclusion, this study will generate important insights 

on a novel, urgently needed response to GBV in a high prevalence setting and is highly likely to 

have a significant public health impact. 

5-R01-TW-008151-03

Molecular epidemiology of drug resistance and population genetic structure of Plasmodium 

falciparum and P. vivax in Yunnan and Hainan, China

Lu, Fangli

Sun Yat-sen University, Guangzhou, PR China

$50,000

The project will be of significant benefit to public health programs aimed at identifying and 

combating drug-resistant malaria, and have the potential to benefit the health of a substantial 

proportion of the world's population. The data will provide valuable information for extending 

the life span of individual antimalarial drugs and developing more appropriate malaria control 

policies in China. Malaria remains a serious public health problem in China. In the subtropical 

Yunnan Province and the tropical Hainan Island of China, malaria has been the most endemic 

with high transmission of both Plasmodium falciparum and P. vivax. However, most of the 

attention in terms of research and interventions has been focused in Africa and Southeast Asia, 

very few studies of malaria in China have been conducted. Because of extensive use, chloroquine 

(CQ) has now lost its efficacy due to the emergence of resistant strains in most parts of the 

world. Meanwhile, suspension of the use of CQ has resulted in reappearance of CQ sensitivity. 

However, there were differences in the evolution of CQ resistance between parasites from 

Yunnan and Hainan, the exact mechanism needs to be investigated. Sulfadoxine-pyrimethamine 

(SP) targets the dhfr and dhps genes of P. falciparum, and point mutations that confer resistance 
54

have been widely reported worldwide. Documenting the identity and extent of SP resistance is 

also critical for policy decisions regarding antimalarial drugs. In addition, P. vivax causes a large 

burden of morbidity in the world including China but traditionally has been understudied. Based 

on these, our long-term goal of this proposal is 1) to identify single-nucleotide polymorphism 

(SNP) and characterize the geographic distribution of genetic diversity, population structure, and 

haplotype variability at drug resistant loci of P. falciparum from Yunnan and Hainan, China, 2) 

to examine the geographic population structure, levels of genetic diversity of P. vivax using 

microsatellite and SNP, and 3) to yield valuable information for making more effective malaria 

control policies in China. In the past several years we have developed the molecular methods to 

study the genetics, population diversity, and evolution of malaria parasites, and have done some 

preliminary studies on malaria field isolates from Yunnan and Hainan using genetic markers, 

thus enabling us to study the molecular epidemiology of these important malaria parasites in this 

proposal. The specific aims are to: 1. Determine genetic polymorphisms associated with CQ 

resistance (CQR) in P. falciparum field isolates from Yunnan and Hainan provinces, China. 2. 

Determine the point mutation prevalence in the dhfr (pyrimethamine drug resistance) and dhps 

(sulfadoxine drug resistance) genes associated with SP resistance in P. falciparum field isolates 

from Yunnan and Hainan provinces, China. 3. Assess the changes of P. vivax genotypes using 

pvcsp, pvmsp1, pvmsp3-1 genes, and microsatellite markers and determine the geographic 

structure and specific epidemiological characteristics of P. vivax transmission in Yunnan and 

Hainan, China. 1 

5-R01-TW-008288-03

Weight, Diet, Genes and CVD Risk Factors (Hypertension and Diabetes)

Lee, Nanette Requintina

University Of San Carlos, Cebu City, Philippines

$50,000

This study will examine the independent and combined effects of genetic predisposition and 

modifiable factors such as weight and dietary patterns on the risks of having hypertension and 

diabetes, two major cardiovascular disease (CVD) risk factors. The demographic and health 

trends in the Philippines exemplify those of other developing Asian countries where CVDrelated morbidities and deaths are prevalent and increasing. Thus, studying the mechanisms that 

can lead to the development of hypertension and diabetes among Filipinos can provide critical 

information that may guide more tailored prevention efforts for these populations, potentially 

narrowing global health disparities. Cardiovascular diseases (CVD) are the leading causes of 

morbidity and mortality in the world (1- 3). Hypertension and diabetes, two of the major CVD 

risk factors, are complex diseases caused by the combined actions of genetic and environmental 

factors (4-8). Few studies have examined the interaction of these factors and fewer, if any, have 

looked at their effects in populations of developing Asian countries that are plagued with 

increasing levels of obesity and rapidly changing food environments (9, 10). The information 

gap may be due to the lack of population-based studies with adequate depth and detail. There is a 

paucity of information on dietary and adiposity trends derived from longitudinal studies and 

there are inadequate genetic data, especially among Asians who tend to develop CVD risk 

factors at lower body mass index thresholds (11, 12). Aims and Methods: The proposed study 

aims to understand how weight history, dietary patterns, and genetic variants independently and 
55

jointly affect blood pressure and fasting glucose among adult Filipino women (ages 38 to 71 yr 

in 2007) using the Cebu Longitudinal Health and Nutrition Survey (CLHNS), an ongoing 

community-based study of over 2000 women (and their infants) which began in 1983. This is a 

unique dataset that contains not only rich genetic information on these women but also dietary 

and anthropometric measurements obtained since baseline, recent blood pressure (1998-2007) 

and fasting glucose (2005) measurements, and other individual-, household-, and communitylevel data collected over a span of 24 years of rapid country-wide socio-economic changes. 

Specifically, using multivariate regression methods we will determine the: (a) effect of weight 

history (i.e. duration of overweight) on the risk of having hypertension and/or diabetes; (b) 

association between dietary patterns (identified through cluster analysis) and hypertension and/or 

diabetes; (c) independence and co-occurrence of hypertension and diabetes and how these relate 

to weight and dietary patterns; and (d) effects of genetic variants on hypertension and diabetes, 

focusing on gene variants that have been associated with hypertension or diabetes by previous 

association studies. Further, the study will explore significant interaction of effects among 

genetic variants, overweight history and dietary patterns in affecting hypertension or diabetes. 

5-R24-TW-008881-02

Novel Education Clinical Trainees and Researchers (NECTAR) Program

Campbell, Thomas B.

University Of Zimbabwe

$60,000

This application for a MEPI Programmatic Award will establish the Novel Education Clinical 

Trainees and Researchers (NECTAR) program at the University of Zimbabwe College of Health 

Sciences (UZCHS). UZCHS is the centre of medical research and education for Zimbabwe. 

NECTAR will be a consortium of investigators based on the long history of strong and 

productive collaborations in education and research between faculty at UZCHS and faculty at 

Stanford University and the University of Colorado Denver. The NECTAR consortium will 

consolidate the unique education and research training experience and expertise available in each 

of the consortium institutions. UZCHS, is the applicant institution and the site of most NECTAR 

activities. The strategy of NECTAR is that improvements in the approach to medical education 

at the medical student and post graduate levels, coupled with programs to improve faculty 

training and support and investments in novel educational models and technologies, will lead to 

improved capacity of UZCHS to meet the healthcare training and research capacity needs of 

Zimbabwe. The goals of NECTAR are to: (1) Increase the number and improve the proficiency 

of UZCHS medical graduates in PEPFAR priority areas. (2) Improve the retention of UZCHS 

graduates in Zimbabwe and increase the proportion of recent graduates who practice in 

Zimbabwe, serve as faculty at UZCHS, conduct research and are engaged in PEPFAR health 

priority areas. (3) Improve the recruitment and retention of academic faculty at UZCHS by 

transforming the UZCHS academic environment, creating new and sustainable educational and 

clinical partnerships and research opportunities.
56

5-R24-TW-008863-02

Enhancing, Training, Research Capacity And Expertise In HIV Care-ENTREE

Lalloo, Umesh G.

University Of Kwazulu-Natal

$60,000

This medical education partnership initiative project will enhance the competency and number of 

doctors, nurses and pharmacists in HIV/AIDS care in KwaZulu-Natal, South Africa which has 

numerous PEPFAR treatment sites. It will contribute to the goal of increasing the quality and 

numbers of patients receiving care. This will be achieved through its HIV/AIDS focused 

programs of undergraduate and postgraduate medical education and academic support for HIV 

treatment platforms and will promote the development of women. The broad aim of the 

Enhancing Training, Research Capacity and Expertise in HIV Care (ENTREE) program is to 

address the shortage of competent health care personnel to manage the increasing burden of 

HIV/AIDS in the Province of KwaZulu Natal that has numerous PEPFAR treatment programs. 

The specific aims are to: increase the competency of medical, nursing and pharmacy students in 

the management of HIV/AIDS through enhancement of undergraduate training and infusion of 

the curriculum with a program of a continuum of care approach to HIV/AIDS and improved 

clinical preceptorship; scaling up of an innovative parallel training track for selected 

undergraduate medical students in HIV towards a certificate / diploma / masters program; 

increase the competency of medical interns / house-officers through the development of a 

program that will create a cadre of master trainers to support and enhance the internship 

experience; create a supportive learning environment and in so doing attract medical trainees to 

return to these centers that include both urban and rural internship and academic and nonacademic clinical service centers; develop and support a program of research to enhance skills, 

among undergraduates and faculty, in research methodology and research implementation with 

particular emphasis on HIV and related complications including individuals selected from 

Southern African Development Community (SADC) countries; develop a program to promote 

retention of academic and research staff by providing a research career pathway and research 

support; and develop a postgraduate medical resource center unit within the Nelson R Mandela 

School of Medicine (NMSM) with seed funding support from the Department of Health training 

grant. At least 50% of the beneficiaries of the program will be women. The program will use and 

expand an established telehealth program and set up academic resource centers in HIV care sites 

in KwaZulu Natal. The project will harness the resources of the academic departments of the 

Nelson R Mandela School of Medicine, the Schools of Nursing and Pharmacy and the 

established HIV/AIDS research units in the University KwaZulu- Natal. The University of 

Columbia is the US partner in this project. 

5-R24-TW-008873-02

Programmatic: Expanding Innovative Multidisciplinary Medical Education in Zambia

Mulla, Yakub F

University Of Zambia

$60,000
57

The people of sub-Saharan Africa are the most heavily affected by the HIV epidemic. The 

Zambian programmes for expansion of HIV therapy and prevention services has been very 

impressive but can only be sustained if more health care workers are trained. The single center 

for most advanced health care worker training in Zambia is the University of Zambia (UNZA). 

We propose to enhance the training programs at UNZA to improve the quality of training 

allowing for training many more HCW throughout Zambia. Zambia is one of the countries in the 

world most heavily impacted by the HIV epidemic with an estimated adult prevalence of 14.3%. 

While recent indicators suggest progress in the national HIV prevention and management 

response, this is not sustainable without substantial increases in health manpower. Health care 

worker (HCW) training will require investments at many levels, starting with the expansion of 

the capacity and quality of pre-service training programs. The University of Zambia (UNZA) is 

the sole training institution in Zambia for Medical Officers and other health care professionals 

including bachelors degree programs in Nursing, Pharmacy, Biomedical Sciences, and 

Physiotherapy, Masters in Public Health and Nursing, and Masters in Medicine for clinical 

subspecialties. UNZA also has active affiliation agreements with the only Clinical Officer 

training program at Chainama College of Health Sciences and with other training institutions for 

nursing and HCW training institutions throughout Zambia. UNZA is thus critical for addressing 

the needs to expand HCW training in Zambia. Critical shortages of faculty and instructors must 

be addressed in order to meet these targets. The overall goal of this programmatic application is 

to strengthen both the quality and quantity of HCW education across selected high-priority 

training programs at UNZA and its partner institutions. Expanding and retaining faculty will be 

critical to these goals long-term. To accomplish this goal, our Specific Aims are: Specific Aim 1: 

Improve substantially the capacity of UNZA to train more HCWs at the UNZA School of 

Medicine (SOM) and affiliated institutions. Specific Aim 2: Improve the overall quality of HCW 

training, emphasizing integrated HIV specific training at UNZA. Specific Aim 3: Enhance the 

MMed degree program for physicians to ensure that graduates have the capacity to conduct 

evidence-based research and program evaluation. Specific Aim 4: Enhance the academic 

environment at UNZA to better retain faculty. 

5-R24-TW-008908-02

The Universidade Eduardo Mondlane/UCSD Medical Education Partnership

Noormahomed, Emilia

Universidade Eduardo Mondlane, Maputo Mozambique

$60,000

Although the development of new curriculum and of new educational approaches has had a 

profound impact on medical education around the world, the biggest challenge to medical 

education in many sub-Saharan Africa countries continues to be that there are too few medical 

educators and that the institutions in which they teach are so poorly supported that they cannot 

fully apply their considerable skills and energy to medical education. Thus, the overriding goal 

of the Universidade Eduardo Mondlane-UCSD Medical Education Partnership is substantially 

increase the number of highly skilled medical school faculty in Mozambique. We will emphasize 

the development of a powerful but locally sustainable biomedical informatics infrastructure to 

enhance both teaching and learning. By strengthening the infrastructure for clinical, operational 

and epidemiological research we will both provide additional avenues for faculty development 
58

and greatly enhance institutional stability. A major priority of this collaboration is to recruit 

trainees and junior faculty into lifelong careers in medical education and to provide them with 

the skills to make these careers sustainable. To this end, we will develop early and mid-career 

mentoring programs that are tailored to the goals of individual Mozambican faculty and trainees 

as well as to the needs of the UEM Faculty of Medicine. Although the partnership will be 

anchored in Mozambique by the Universidade Eduardo Mondlane, as the program develops we 

will provide active assistance to Mozambique's two new medical schools in Nampula and Tete to 

create a network of all three of Mozambique's publicly funded Faculties of Medicine in order to 

extend the impact of this MEPI to all of Mozambique. By substantially strengthening 

Mozambique's medical education infrastructure, we expect that our partnership will have a 

profound effect on Mozambique's ability to deliver better medical care to all of its citizens for the 

next several decades.

5-R24-TW-008886-02

Medical Education for Services to All Ugandans (MESAU)

Sewankambo, Nelson K

Makerere University, Kampala, Uganda

$60,000

Improving medical education in resource-limited settings through Innovative curricula will result 

in a larger number of high quality health care workers with the competencies to address Ugandan 

health care priorities such as HIV/AIDS and non-communicable disease such as cardiovascular 

disease and cancer. In Africa, HIV, infectious diseases and other severe health problems 

compounded by critical shortages of health workforce compromise effective health care delivery. 

In order to train the necessary number of medical doctors in Africa, medical schools need to 

produce more high quality doctors. This proposal assembles a 5 Ugandan medical school 

consortium with JHU to catalyze capacity building and performance enhancements in medical 

education, research, and environment geared towards improved service delivery. Funding this 

proposal will facilitate Ugandan universities to strengthen countrywide south-south institutional 

collaboration as a strategy to enhance quality in medical education with an increase in the 

number of health workers trained and retained in the country, especially in rural areas. This 

funding will strengthen the capacity of the Ugandan medical schools consortium to realize their 

joint mission "to ensure the transformative innovative medical education built on strong 

sustainable systems to produce more health workers of consistently high quality to address health 

priorities like HIV/AIDS through service and research to improve health outcomes for Uganda." 

The specific aims of the proposal are to improve the quality and relevance of medical education 

and service training by developing learner-centered curricula to be implemented at standardized 

community-based platforms for education, service, and research which geographically cover the 

entire country. Well-trained on-site supervisors will teach competencies necessary to deliver 

locally relevant services in resource-limited environments. Next, incentives and support will be 

provided to faculty and students to undertake transdisciplinary research at the community-based 

sites. A series of grants will be offered that will give students the opportunity to initiate 

operational research at community sites, will increase the pipeline of basic science and family 

medicine advanced degrees, and encourage faculty development and retention through research 
59

grants with "twinning" opportunities with JHU faculty. Finally, support systems capacity 

building will be emphasized to facilitate the efficient conduct of education and research. 

HIV

5-R21-AI-082689-02

Development of Antimicrobial Peptides as Topical Microbicides

Buckheit, Robert W

ImQuest BioSciences

$21,428

We hypothesize that novel anti-HIV and anti-STI topical microbicides based on natural 

antimicrobial peptides collected in the Antimicrobial Peptide Database developed by the co-PI's 

laboratory (http://aps.unmc.due/AP/main.html) can be discovered and improved through peptide 

engineering technology. During the R21 phase, we will methodically screen peptides from the 

database and define specific inhibitors of HIV and HSV-2 as well as broad based inhibitory 

peptides. These active agents will be further developed in order to understand their range and 

mechanism of anti-HIV action. Superior peptides identified in SA1 will be characterized in SA2 

to provide a rationale for continued development in SA3 using various molecular strategies 

which will result in the improvement of the therapeutic index of the peptide agents, with and 

without other small molecule microbicides, in order to begin development of an effective 

microbicide product. This product will be formulated and evaluated in animal models and safety 

assessment studies in the R33 portion of the project. Our goal is to produce a female controlled 

preventative agent which can be utilized to prevent the sexual transmission of viral, bacterial and 

fungal organisms with a focus on inhibiting the transmission of HIV. The research data will be 

entered into the existing antimicrobial peptide database to facilitate the use by funding agencies, 

other researchers, students and the public.

5-R21-AI-088601-02

Targeted siRNA Delivery As An Anti-HIV Microbicide

Dykxhoorn, Derek Michael

University of Miami School of Medicine

$21,428

Human immunodeficiency virus (HIV) is a highly lethal lentivirus which over a protracted 

course destroys the host's adaptive immune system leaving them vulnerable to numerous 

opportunistic infections. Unlike most viruses whose genome replicates independently of the host 

cell's genome, the HIV-1 genome integrates into and is replicated with the host genetic material. 

Therefore, even if therapeutic approaches can inhibit new virus production, the viral genome 

remains intact and competent. Therefore, strategies that can prevent the uptake and integration of 

the virus would be of tremendous clinical value. The vast majority of HIV infections occur as a 

consequence of viral transmission through mucosal surfaces, such as the vaginal mucosa. The 

delivery of siRNAs that specifically silence host factors required for early events in the HIV life 
60

cycle to lymphocytes in the vaginal mucosa could prove to be an effective means of protecting 

individuals from HIV infection and serve as a potential microbicide. One of the main challenges 

facing the clinical application of siRNAs as a genetic therapy is the ability to delivery siRNAs to 

the cytoplasm of the appropriate target cell types. We have recently developed a novel lipid 

nanoparticle that is coated with an antibody recognizing the integrin molecule LFA-1 which is 

broadly expressed on lymphocytes. These immuno-nanoparticles will be used to deliver siRNAs 

to lymphocytes present in the vaginal mucosa of humanized mouse models of HIV. Given the 

high level of sequence heterogeneity, the propensity of HIV-1 to mutate and the inability of antiHIV siRNAs to target the incoming viral RNA genome and prevent integration, alternative 

therapeutic targets are required to prevent the transmission of HIV. Host factors that are 

necessary for early events in the HIV lifecycle but are dispensable for cellular functioning could 

prove to be an effective therapeutic alternative. Using a high-throughput RNA interference-based 

screening platform, we have identified a large number of potential therapeutic targets that could 

serve to inhibit HIV integration when silenced. However, these factors require extensive analysis 

and characterization to ensure their safety and efficacy. We will be combining the LFA-1-

mediated cell-type specific vehicle to introduce siRNAs targeting therapeutically relevant host 

factors as a potential means to inhibit viral infection in humanized mouse models of HIV. These 

experiments will provide the preclinical groundwork necessary for the development of an 

effective RNAi-based anti-HIV microbicide. Heterosexual transmission is the leading cause of 

new HIV infections in the world. A microbicide providing true intracellular immunity would 

make a significant contribution to controlling the spread of this deadly virus.

5-R21-AI-088586-02

Development of a novel nanoparticle pyrimidinedione vaginal polymeric film as an antiHIV microbicide

Ham, Anthony Sang Won

ImQuest BioSciences

$21,428

Pyrimidinediones (PYD) are highly potent small molecule inhibitors that have a dual anti-HIV 

mechanism of action: viral entry inhibition and non-nucleoside reverse transcriptase inhibition 

(NNRTI). The PYD compounds have shown in vitro subnanomolar levels of activity as an 

NNRTI and nanomolar levels of activity as inhibitors of entry occurring prior to chemokine 

receptor binding and fusion. However, as microbicides compounds are being developed, delivery 

issues that are part of the formulation of the compound have lagged behind causing a critical 

delay in product development. Due to low solubility and poor penetration through the mucosa to 

the target site of action, Pyrimidinediones face significant obstacles as microbicides. Strategic 

drug delivery design is essential for Pyrimidinediones to advance as viable microbicide products. 

We propose a combination of innovative drug delivery strategies to enhance PYD anti-HIV 

efficacy through polymer biochemistry formulations. Specifically, nanoparticle encapsulation 

has been used to overcome many of the challenges presented when using hydrophobic drug 

molecules; however, its use as a vaginal drug delivery system has not been investigated. In the 

R21 phase of this project, we propose to develop nanoparticle encapsulation of PYD as a novel 

drug delivery method to improve the potency of HIV inhibition activity by increasing long term 

drug release, protecting against enzymatic degradation, enhancing submucosal tissue penetration 
61

and cell localization. Additionally, we propose to further formulate the nanoparticle PYD 

formulation into a vaginally delivery polymer film dosage form. Such "quick dissolving" solid 

dosage forms have recently been proposed as a innovative alternative to address several 

acceptability and compliance issues observed in more traditional vaginal delivery systems (gels, 

creams, intra-vaginal rings). Our nanoparticle PYD film delivery approach offers several 

innovative advantages in microbicide development by suggesting enhanced apparent activity 

without active pharmaceutical ingredient (API) reformulation, conferring HIV protection over 

long periods of time through controlled drug release, making such a microbicide coitallyindependent, and introducing a novel drug delivery method through vaginal films that addresses 

many of the acceptability issues with gels and other semi-solid dosage forms. Biological 

characterization and evaluation will be preformed to confirm the efficacy of PYD nanoparticles 

in biologically relevant conditions. The encapsulation of PYD into biodegradable nanoparticles 

will be characterized and evaluated in specifically designed in vitro assays to determine drug 

targeting and release. Additionally, the anti-HIV efficacy of the nanoparticle PYD will be 

compared to unformulated PYD in biologically relevant in vitro assays to determine the optimal 

formulation. Finally, the formulation will be introduced into a solid vaginal film dosage form to 

evaluate its biological properties in HIV prevention.

5-R21-AI-082680-02

Phosphorothioate Oligonucleotides as Microbicides against HIV Transmission

Katsikis, Peter D

Drexel University

$21,428

Developing interventions that inhibit the transmission of HIV infection are critical for halting the 

HIV epidemic. Topical prevention strategies usually termed microbicides have been proposed as 

one strategy to halt or slow down the HIV epidemic. We have identified novel lead microbicides 

that potently inhibit HIV and SIV infection/replication in vitro. During our previous submission 

we reported an oligonucleotide with a phosphorothioate backbone (OPB) that could inhibit 

HIVBaL or SIVmac251 infection and/or replication in human or simian PBMC, respectively. 

OPB also inhibited infection/replication in cell-free infections of P4-R5 MAGI cells by HIVBaL 

and HIVIIIB. OPB exhibited no toxicity against PBMC or P4-R5 MAGI cells after 24h 

continuous exposure. Preliminary data suggested that OPB may also inhibit other viruses as it 

was also effective against influenza type A virus. Thus, our first generation OPB may be a potent 

microbicide against HIV that prevents infection at mucosal sites when topically applied. Our 

preliminary studies were carried out with a 13mer Poly T or Poly A oligonucleotide of OPB and 

this suggested that the effect was sequence independent and may even be mediated by the 

phosphorothioate deoxyribose sugar backbone. Indeed in our current re-submission we present 

data on our next generation compound, a baseless phosphorothioate 2' deoxyribose backbone 

(PDB) that has more potent HIV inhibitory activity than OPB. A 14mer PDB we show here has 

no toxicity, is a potent inhibitor of HIV and has the advantage of being a TLR7/9 antagonist that 

inhibits HIV-induced IFN¿ production. This later property is important as the establishment of 

HIV infection may depend on HIV-induced mucosal inflammation triggered by TLR. 

Importantly, we show that PDB is active when formulated in hydroxyethylcellulose (HEC) gel at 

pH 4.4, survives pH transition to a neutral pH, and in retains its activity in HEC for long periods. 
62

We hypothesize that PDB binds enveloped viruses and inhibits their infectivity by acting as a 

"chemical lectin". We further hypothesize that PDB can act as a microbicide against HIV and 

can prevent SIV vaginal infection of rhesus macaques. The studies planned in the R21 phase will 

further optimize and characterize the safety and effectiveness of PDB in vitro and its safety in the 

Swiss Webster mouse vaginal/cervical model of irritation. They will determine the optimal size 

and composition that remains effective against HIV and exhibits no toxicity. Finally, the 

mechanism of action of PDB will be investigated, the effect of inclusion into 

hydroxyethylcellulose gel will be tested and PDB's effect on the growth of commensal 

lactobacilli will be determined. Five specific milestones have been set for the progression from 

the R21 Phase to the R33 Phase. The R33 phase will test the effectiveness of PDB in preventing 

vaginal SIV infection, investigate the effect of seminal plasma and pH transition on the efficacy 

of OPB, determine its safety with human genital epithelial tissue, and investigate its 

effectiveness against HSV-2. The current application will allow for an extensive evaluation of 

PDB as possible novel microbicide candidates. The studies proposed here address the important 

public health problem of developing treatments that inhibit the transmission of HIV infection. 

The current application investigates a novel chemical that may be used to inhibit infection with 

HIV.

5-R21-AI-088585-02

Plant-produced Actinohivin as a Candidate HIV Microbicide

Matoba, Nobuyuki

University of Louisville

$21,428

Safe, effective, and inexpensive topical microbicides are urgently needed to curb the global 

human immunodeficiency virus type-1 (HIV-1) epidemic. Actinohivin (AH) is an actinomycetederived lectin. This lectin specifically binds to high-mannose clusters uniquely found on the 

HIV-1 envelope (Env), thereby eliciting nanomolar antiviral activity against multiple HIV 

strains. Preliminary analyses revealed that AH has a high safety profile in human peripheral 

blood mononuclear cells (PBMCs) and in the rabbit vaginal irritation assay. Meanwhile, a 

translational AH-AH fusion protein (recombinant dimer [rd] AH) was suggested to have stronger 

and broader anti-HIV-1 activity than the original monomer. Given these high potentials, we 

hypothesize that rAH and/or rdAH (r/rdAH) are excellent HIV-1 microbicide candidates. This 

project's goal is to reveal the feasibilities of r/rdAH in terms of manufacture, antiviral efficacy, 

and safety upon use as a vaginal microbicide. In the R21 phase, we will initially focus on 

developing a highly efficient, scalable production system for r/rdAH that allows for extensive 

efficacy and safety studies and possible global use. We will utilize recombinant plant virus-based 

expression systems and various molecular biological approaches for rapid and high-level 

expression of high-quality r/rdAH. Upon obtaining bulk r/rdAH active pharmaceutical 

ingredients with high purity standards, we will analyze HIV-1 neutralization effects against 

selected R5-type viruses in two in vitro HIV neutralization assays based on Env-pseudotyped 

virus-reporter gene expression and primary isolate- PBMC infection systems. Next, r/rdAH' 

cytotoxic, mitogenic, and inflammatory potentials will be tested in PBMCs and/or human 

cervicovaginal (CV) epithelial cell lines to establish the minimal safety profile. Our success 

criteria in the R21 phase are: (1) establishing the bulk preparation procedure; (2) demonstrating 
63

cross- clade antiviral effects to R5 viruses; and (3) demonstrating no apparent in vitro 

cytotoxicity, mitogenic activity, or inflammatory potential at >100 times above an average antiHIV IC50, for plant-made r/rdAH. Upon approval of our transition to the R33 phase, we will 

comprehensively analyze anti-HIV-1 efficacy of r/rdAH for various modes of HIV-1 infection 

and transmission, using various in vitro assay systems. In addition, we will investigate potential 

overlap, complementation, synergy, and antagonism of anti-HIV activities between r/rdAH and 

other inhibitors toward potential microbicide combination strategies. Finally, we will perform 

extensive evaluations of r/rdAH upon vaginal application in rabbit and mouse models. We will 

thoroughly evaluate r/rdAH' vaginal toxicity, inflammatory potential, and stability. Upon 

determining the maximal tolerated dose of r/rdAH, we will examine their potential 

immunogenicity and toxicity after a long-term exposure. Potential toxicity to the symbiotic 

vaginal commensal bacteria, the Lactobacillus species, will be examined. In summary, the 

proposed studies should answer the question of whether r/rdAH is justified for advanced nextstage preclinical studies. . The proposed studies will analyze the feasibilities of the novel HIV-1-

binding lectin Actinohivin and its derivative recombinant dimer, as a candidate vaginal HIV-1 

microbicide. The proposed studies should generate a comprehensive data set that will reveal their 

large-scale producibility, anti-HIV-1 efficacy, and broad toxicity profile upon vaginal 

application, thereby providing criteria of whether Actinohivin and its derivative are justified for 

further extensive preclinical and clinical studies.

5-R21-AI-088597-02

Engineering Antiviral Innate Immunity For Safe And Effective Microbicides

Shen, Hong

University of Washington

$21,428

HIV infections afflict millions of people and cause tremendous health and economic burdens. 

One of the major risk factors for HIV-1 transmission is the pre-existing infections caused by 

sexually transmitted agents such as herpes simplex virus type 2 (HSV-2). Therefore, a rational 

prevention strategy to halt HIV spread is to target HSV-2 infection and control its spread. In the 

absence of vaccines against HSV-2, a more practical and effective intervention for HSV-2 is the 

utilization of microbicides. A promising microbicidal approach is to potentiate antiviral innate 

immunity effective against a broad range of viruses at the site of viral encounters. The toll-like 

receptor (TLR)-based innate immunity have been shown to be crucial in initiating a cascade of 

antiviral activities mediated by type I interferons (IFNs). Both TLR3 and TLR9 agonists, 

polyinosinic: polycytidylic acid (poly IC) and CpG oligonucleotides (ODNs) are effective in 

protection against HSV-2 infections. However, undesirable inflammatory responses and 

autoimmunity accompanying the non-specific stimulation of TLRs are of major concern, which 

could severely limit the use of TLR agonists as microbicides. Thus, the key to developing TLR 

agonists as microbicides is to target them to relevant cell types at the potential sites of viral 

exposure and to elicit IFN responses in a regulated fashion. We propose to develop localized, 

controlled-release, and cell-targeted delivery systems to regulate the stimulation of TLR-based 

innate antiviral immunity. In the R21 Phase, three aims will be accomplished: Aim 1: to design 

and characterize cell-targeted delivery systems based on poly (lactide-co-glycolide) (PLGA) 

nanoparticles to specifically and locally target pDCs and epithelial cells with TLR agonists; Aim 
64

2: to evaluate the effectiveness against genital HSV-2 infections by locally and selectively 

targeting CpG ODNs and/or poly ICs to pDCs and epithelial cells with cell-targeted 

nanoparticles; Aim 3: to evaluate toxicity by locally and selectively targeting CpG ODNs and/or 

poly ICs to pDCs and epithelial cells with cell-targeted nanoparticles. Built upon the results from 

the R21 phase, in the R33 phase, we will accomplish: Aim 4: to design and characterize delivery 

systems for sustained release of TLR agonists; Aim 5: to evaluate the effectiveness against 

genital HSV-2 infection and toxicity by localized, sustained-release and cell-targeted 

nanoparticles loaded with CpG ODNs and/or poly IC; Aim 6: to evaluate the adaptive immunity 

against genital HSV-2 infection mediated by localized, sustained-release and cell targeted 

nanoparticles loaded with CpG ODNs and/or poly IC. This application will enable the translation 

of TLR-based antiviral innate immunity to effective and safe microbicides.

2-R21-AI-088595-02

Exploring the Role of Vif Antagonists in Preventing Sexual HIV Transmission

Stevenson, Mario

University of Massachusetts Medical School

$21,428

Since it has proven difficult to develop a vaccine against HIV-1, the major cause of the AIDS 

pandemic, the research community has shifted some of its focus to the development of topical 

microbicides. Since both the vaginal and rectal tract are portals of HIV-1 entry, topical 

microbicides suitable to protect both sites need to be developed. In this grant, we focus on a 

novel mechanism that has not previously been explored for HIV prevention. In 2002, it was 

found that the cellular target of the HIV-1 protein Vif is APOBEC3G (A3G). A3G is an enzyme 

of the AID/APOBEC family, characterized by the targeted deamination of cytosine to generate 

uracil within DNA. APOBEC3G plays an important role in retroviral defense by acting on viral 

reverse transcripts and mediates numerous critical immune responses. We believe that A3G is an 

important innate retroviral defense mechanism in the vaginal and rectal tract. By using inhibitors 

of the viral protein Vif, the Vif-APOBEC3G interaction is blocked and APOBEC3G is not 

degraded by the proteosome. As a consequence, fatal hypermutations are introduced into the 

viral cDNA transcripts and HIV is rendered incompetent for replication. Our grant has four 

specific aims: Specific Aim 1: Explore the role of the restriction factor A3G in mucosal tissues 

of the vaginal and rectal tract Specific Aim 2: Examine whether RN18 and its analogs are active 

in microbicide cell-based assays and ex vivo explant HIV transmission models Specific Aim 3: 

Vaginal humanized BLT mouse model testing of promising Vif inhibitor candidates Specific 

Aim 4: Macaque microbicide model testing of promising Vif inhibitor candidates It is expected 

that these studies will define the role of A3G in the vaginal and rectal tract and whether 

inhibitors of the viral Vif protein can prevent sexual transmission of HIV.
65

5-D43-TW-001039-12

AIDS International Training and Research Program

Adimora, Adaora A 

University Of North Carolina Chapel Hill

$20,000

Fogarty trainees are serving in key leadership positions and are in the center of exciting and 

critical research activities. Working with their collaborating institutions they have assessed the 

priority health needs of their partner countries and propose a research training program that 

addresses the countries' research needs as well as the developmental plans of their collaborating 

institutions. This is the second competitive renewal application for the UNC AIDS International 

Training and Research Program. They propose to continue to provide training in three countries: 

The Peoples Republic of China, Malawi and Cameroon. Investigators at UNC have worked in 

China since 1979, Malawi since 1989, and Cameroon since 1998. The UNC AITRP has 

embraced several guiding principles. First, they use training to build strong ties to key in-country 

organizations. Trainees with guaranteed "return jobs" in these organizations are preferentially 

selected. Second, their training opportunities build on funded research projects and bridge many 

of the strengths of UNC. Wherever possible they combine basic, clinical and epidemiological 

training and research in order to build critical mass. Third, they have used the Fogarty training to 

promote international research, working with many collaborators and funding agencies. Fourth, 

they have developed south-to-south and international collaborations to facilitate training and 

ongoing research opportunities. For example, University of the Witwatersrand is a training site 

for Malawi personnel, and they have developed a strong collaboration with the London School of 

Hygiene and Tropical Medicine for training of physicians from Malawi (a former British 

protectorate). Fifth, they have looked for opportunities for evolution and innovation. Such efforts 

have been particularly important in the development of a new Department of Public Health at the 

Malawi College of Medicine (which has received dedicated Fogarty support), extensive research 

ethics and IRB training in China, and rapid technology transfer in all three UNC AITRP 

countries. Sixth, they are committed to in- country leadership and ongoing mentorship after the 

trainee has completed their program. 

5-D43-TW-001042-12

Emory AIDS International Training and Research Program

Del Rio, Carlos 

Emory University

$20,000

Located in Atlanta, the Emory AIDS International Training and Research Program (AITRP) has 

established itself as an interdisciplinary training environment, that is producing highly qualified 

HIV/AIDS researchers. The collaborating countries of the Emory AITRP proposed for this 

application are Mexico, Georgia, Vietnam, Rwanda and Zambia. The specific aims of the 

research training program include: 1. To build academic capacity in partner countries through the 

support of in-country education and training. 2. To build HIV/AIDS research human resource 

capacity through the support of degree-seeking, long-term training. 3. To fill identified gaps in 

partner country research training capacity through the provision of specialized medium and 
66

short-term training. 4. To build in-country capacity to conduct implementation science research 

that will allow their trainees to become involved in the evaluation of the impact of a variety of 

interventions that are currently occurring in their collaborating countries such as PEPFAR.

5-D43-TW001038-12 

AIDS international Training and Research Program

Harrison, Lee H.

University of Pittsburgh

$20,000

The proposed Pitt AITRP training will substantially enhance the ability of Brazil, Mozambique, 

and India to conduct crucial HIV prevention research. They propose to continue the AIDS 

International Training and Research Program (AITRP) at the University of Pittsburgh (Pitt). 

Their mission is to provide Brazilian, Indian, and Mozambican health professionals with 

multidisciplinary tools needed to conduct cutting-edge HIV prevention research in their 

countries. The Director and Co-Director are, respectively, Dr. Lee Harrison, Professor of 

Epidemiology and Medicine, and Dr. Phalguni Gupta, Professor of Infectious Diseases and 

Microbiology. An exciting change in their program is the addition of a site in Beira, 

Mozambique, which has striking training needs and where Pitt has established close 

collaborations with the Universidade Catolica de Mozambique. The addition of Mozambique and 

the training of a large cadre of well-trained Brazilian investigators over the past ten years allow 

us to dramatically reduce their training efforts in Brazil and shift resources to Mozambique. As a 

component of their training program, they will leverage the extensive training already provided 

to Brazil by conducting south-to-south training between these two Portuguese-speaking 

countries. Ongoing research in Brazil includes HIV vaccine trials, studies of effectiveness of 

antiretroviral therapy in public clinics, and changes in causes of death among HIV-infected 

patients. In India, ongoing projects include studies of genetic heterogeneity of Indian HIV 

strains, CDS suppression of HIV, HIV incidence studies to identify high- risk populations, and 

development of a novel Clostridium perfringens-based oral HIV vaccine. Research at their new 

site in Mozambique is currently limited and they will use the training provided by the Pitt AITRP 

to jump start a much-needed research agenda there. Trainees from all three countries will have 

access to the substantial HIV research activities at Pitt, including research in epidemiology, 

behavioral sciences, and laboratory sciences. During the next five years, they propose to 

establish an extensive training program in Mozambique; provide limited, selected training for 

Brazil; and provide laboratory and behavioral sciences training for India. Their successful track 

record during the first 10 years, the excellent training opportunities they propose, and 

collaboration with key institutions in their three countries assure that their program will continue 

to be highly productive. 
67

5-U2R-TW-006896-08

Haiti AIDS Research Training: Models to Implementation

Pape, Jean William

Gheskio Center, Port-Au-Prince, Haiti

$20,000

The specific areas of integrated clinical, operational, and health services research that will form 

the basis of the proposed ICOHRTA training program include: 1) adult antiretroviral treatment; 

2) prevention of mother to child HIV transmission and antiretroviral treatment of HIV- infected 

mothers and infants; 3) tuberculosis with emphasis on multidrug resistant TB and HIV coinfection; 4) AIDS malignancies; 5) adolescents and HIV/AIDS; and 6) behavioral research. 

Research training will focus on translating models of HIV and TB care and prevention to largescale national implementation. The goal of GHESKIO-Cornell ICOHRTA training program is to 

increase capacity in integrated clinical, operational, and health services research in support of 

Haiti's national scale-up of HIV and tuberculosis services. Haiti is the poorest country in the 

Western Hemisphere and has the highest rates of both HIV infection and tuberculosis. It is 

estimated that 3% of the adult population isHIV- infected and that the prevalence of tuberculosis 

is 402/100,000 population (100xUS rates). In response to this epidemic, the Haitian Ministry of 

Health asked GHESKIO to form a national HIV and TB Network, a collaboration of 32 public 

and private health care organizations across the country that is charged with "scaling-up" to 

provide a standardized package of HIV and tuberculosis services to 500,000 persons by 2014. 

The services include voluntary counseling and HIV testing, management of tuberculosis and 

sexually transmitted infections, prevention of mother to child HIV transmission, and 

comprehensive HIV care of children, adolescents, and adults. The Haitian Ministry of Health has 

asked GHESKIO (Haitian Study Group for the Study of Kaposi's Sarcoma and Opportunistic 

Infections) to lead this network through training, supervision, monitoring and evaluation, and 

through the conduct of operational and health services research. GHESKIO is an international 

research and training institution that has benefited from 25 years of uninterrupted NIH funding 

and research capacity building with Cornell University, and support from the Fogarty 

International Center. GHESKIO is recognized as a center of research excellence, and is a 

member of the NIH HIV Vaccine Trials Network (VTN), the AIDS Clinical Trials Group 

(ACTG) and a recipient of support from the United Nations Global Fund for AIDS, TB and 

Malaria and the President's Emergency Plan for AIDS relief (PEPFAR). In the current proposal, 

GHESKIO will continue as the primary training institution and extend research capacity to other 

organizations in Haiti that are participating in the GHESKIO HIV and Tuberculosis Network. 

The program will continue to emphasize medium- and long-term training in Haiti. Since its 

inception four years ago the ICOHRTA has provided training to 120 Haitian biomedical 

personnel, all of whom are working in Haiti, providing HIV/TB services and conducting 

operational and health services research. GHESKIO, in collaboration with Haitian and 

International partners, will develop training curricula in clinical, operational, and health services 

research methodology and in ethics, program management, and scientific writing. A Masters in 

Public Health Degree program, established with ICOHRTA support, will continue to be offered 

in Haiti by Quisqueya University, in partnership with GHESKIO and Cornell University. 
68

5-D43-TW-001035-12

Vanderbilt University-CIDRZ AIDS International Training And Research Program

Vermund, Sten H 

Vanderbilt University

$20,000

The Vanderbilt University (VU)- Center for Infectious Disease Research in Zambia (CIDRZ) 

training partnership with their international collaborators is designed to strengthen both 

institutional and individual biomedical and behavioral research capacities focused on HIVrelated research in both prevention and care in developing countries. The VU-CIDRZ AITRP, 

formerly the VU-University of Alabama at Birmingham AITRP, seeks renewal of its grant, now 

in its tenth year due to an NIH-initiated one-year extension. They contribute research training to 

both institutional and individual biomedical and behavioral research capacities focused on HIVrelated research in both prevention and care. The VU-CIDRZ training partnership with their 

international collaborators is designed to train foreign scientists and key research support staff to 

conduct independent research and training in their home countries, as well as perform at an 

internationally credible level in collaborations with local and foreign scientists. They now seek to 

renew their AITRP with a continued focus on Zambia (since 1998), Pakistan (since 1994), India 

(since 2000), China (since 2000), and their newest partnership in Mozambique (VU training 

partnership since 2006 and developmental AITRP engagement since 2007). They have 

completed their older training commitments in Mongolia, Jamaica, and Russia and will complete 

their training commitments for Bangladesh upon the graduation of a current doctoral training 

(anticipated in 2011). They have restricted their AITRP training partnerships to five focus cities 

in order not to dilute their impact to where they have funded overseas research and strong 

research training partners. At the same time, they have leveraged support in each of the five 

venues such that their AITRP resources will go much further than permitted by the grant's 

funding alone. They will continue to provide a diverse portfolio of long, medium, and short-term 

training options. To date 58 trainees have received graduate degrees, 97% of whom have 

returned to work in their home countries, 8 are currently in degree programs and over 2,000 have 

been trained through their in-country advanced short- courses. They believe VU remains an ideal 

university partner for this initiative for several significant reasons.The migration of the training 

program to VU offers the opportunity for trainees to receive the absolute highest quality of 

graduate training and exposure to innovative HIV/AIDS/STD/TB related research, resources, and 

faculty mentors. The program is uniquely positioned within the infrastructure of the VU Institute 

for Global Health (VU IGH),directed by Dr. Vermund with its "center-without-walls" 

philosophy that nurtures noncompetitive partnerships among and within VU and with partner 

institutions around the globe. They feel that the innovative features of their renewal and their 

proven track record address the unmet needs in international AIDS training. 
69

1-R21-AI-094412-01

Nanoparticle Microbicides For Delivery Of Combination Antiretroviral Drugs

Woodrow, Kim A.

University of Washington

$18,750

Women are disproportionately impacted by the HIV epidemic and access to female-controlled 

prevention methods such as an effective topical microbicide is critical. To overcome challenges 

associated with formulating multiple anti-HIV compounds in a topical gel, we propose a single 

topical strategy that uses particulate-based microbicides to encapsulate individual agents that are 

delivered in combination. This approach will empower and provide women with an effective 

means of protecting themselves against sexual HIV-1 infection. Sexual transmission through the 

genital tract or rectal mucosa is the most common route for acquiring new HIV infections and 

accounted for ~70% of the 2.7 million people worldwide who became newly infected in 2007. A 

cure or effective vaccine that would contain the global spread of this epidemic is not expected in 

the near term, and new HIV infections continue to outpace advances made in treatment with 

antiretroviral drugs. There is consequently an urgent need to develop agents that can be applied 

topically to mucosal surfaces to prevent the sexual transmission of HIV. However, several largescale clinical trials testing the efficacy of agents that disrupt the integrity of the viral envelope 

(detergents) or prevent adsorption or fusion of the virus with its target cells (polyanions) have 

failed to protect against HIV infection. The success of highly active antiretroviral therapy 

(HAART) provides a paradigm for developing the next generation of microbicides, raising the 

possibility that a combination of potent and broadly active inhibitors that exhibit multiple and 

complementary mechanisms of action may be vastly superior to the delivery of single 

compounds. To fully realize the potential of these potent antiretroviral (ARV) drugs, the 

challenges of formulating and delivering compounds with markedly different chemical stability 

and aqueous solubility in a topical combination product must be overcome. This research plan is 

designed to evaluate nanoparticle-based vaginal drug delivery systems for HIV prevention. The 

experimental focus is to achieve protection against vaginal transmission of HIV-1 by topical 

delivery of a combination of antiretroviral drugs using mucus- and tissue-diffusing nanoparticle 

microbicides. This research would be the first to control the temporal and spatial co-delivery of a 

combination of antiretroviral agents that have different mechanisms of action against HIV-1 

(Aim 1). If successful, our studies would be the first to determine the size range and penetration 

depth accessible for nanoparticulate drug delivery systems in the vaginal mucosa (Aim 2). Our 

proposed research will also provide valuable data on the transport, biodistribution, and 

pharmacokinetics of encapsulated and released antiretroviral agents that are administered 

topically to the vaginal mucosa using nanoparticle microbicides (Aim 3). Finally, we will 

conduct preclinical safety and anti-HIV efficacy studies to rapidly advance our nanoparticlebased microbicides to human safety and efficacy trials (Aim 4). The outcomes from our 

proposed research may highly impact the field of microbicide research for HIV and other 

sexually-transmitted infections. 
70

1-R21-AI-094508-01

Thermostable Vaginal Probiotic Microbicide

Bronshtein, Victor

Universal Stabilization Technologies, San Diego, CA 

$18,750

As the number of individuals living with HIV continues to rise and a feminization of the 

epidemic is occurring. At the end of 2007 women accounted for 50% of all adults living with 

HIV worldwide and 61% in sub-Saharan Africa. Of new HIV cases at least half are in 

individuals less than 25 years of age and of those aged 13-19 54% are teenage girls. For this 

reason there is a desperate need for the development of an effective female controlled 

microbicide product to protect against acquisition of HIV. The innate vaginal flora provide a 

natural defensive barrier to infection hence a probiotic microbicide provides a promising strategy 

for prevention. This project serves to evaluate a strategy to overcome two barriers to its 

successful application, long term bacterial preservation at relevant environmental conditions and 

a user acceptable stable delivery system for vaginal administration. The innovative combination 

of preservation by vaporization and thin film dosage forms with use of multi-strain formulations 

provides a unique technology which can serve to overcome existing barriers to provide a safe 

and effective probiotic microbicide product to protect women from acquisition of HIV. Recently 

revised statistics show the number of individuals living with HIV at over 33 million worldwide, 

with 68% being in sub-Saharan Africa. Current HIV prevention methods, such as condom use, 

monogamy and abstinence, are not always feasible. The need for improved HIV preventative 

technologies remains urgent. The development of topical microbicides represents a new and 

exciting field in the prevention of sexually transmitted diseases. Of these, application of live 

probiotic bacterial microbicides (PBM) represents a promising preventative method. Our 

ultimate goal is to develop potent optimized multistrain thermostable and easily deliverable 

probiotic vaginal topical microbicides. To achieve this goal we will stabilize vaginal probiotics 

for long-term storage at high ambient temperatures and short term survival at temperatures 

required for quick dissolve film manufacturing (60C and above). The cornerstones of this 

proposal are: 1) Preservation by Vaporization" (PBV) - an innovative, patent pending method of 

dry-stabilizing probiotics bacteria and other fragile biologicals at high ambient temperatures, and 

2) Quick-dissolve thin film technology that is being optimized to deliver conventional vaginal 

microbicides. The strategy can be described briefly as, to occupy the vaginal epithelium and 

provide a long lasting protective environment against HIV, BV, and STI acquisition small glassy 

sugar particles containing PBV vaginal probiotic bacteria will be formulated into thin films 

which utilize a water soluble polymer base. Thin films offer a unique delivery platform which 

has a number of advantages over other dosage forms. In a recent study comparing women's 

preference between films, tablets and ovules, the film dosage form was shown to have greatest 

acceptability among women studied. We believe that women will prefer using a vaginal film 

over other potential methods of probiotic microbicide delivery especially if a long-acting effect 

of the bacteria colonizing vaginal epithelium allows for less frequent use. Biologic properties of 

PBM after long-term storage at ambient temperatures will be characterized using cell culture 

models of vaginal and cervical epithelium. 
71

1-R21-AI-094511-01

The Semen Enhancer of HIV Infection as a Novel Microbicide Target

Dewhurst, Stephen

University of Rochester

$18,750

New approaches to prevent the transmission of human immunodeficiency virus type-1 (HIV-1) 

are urgently needed. This application seeks to develop a new class of microbicidal agents that are 

targeted not to the virus itself, but to a host protein found in semen that strongly enhances HIV-1 

infection. This high risk, high reward approach is fundamentally different from traditional 

microbicidal strategies that target the virus, and is expected to be highly complementary with 

direct antiviral approaches. Human semen contains cationic amyloid fibrils, termed the "Semen 

Enhancer of Virus Infection" (SEVI), which strongly enhance HIV-1 infection and may play an 

important role in viral transmission. Our preliminary data show that amyloid-binding molecules 

bind to SEVI, and block semen-mediated enhancement of HIV-1 infection. This suggests that (i) 

SEVI is responsible for semen-mediated enhancement of HIV infection and (ii) SEVI represents 

a novel microbicide target. We therefore propose to explore a novel, innovative approach to 

HIV-1 microbicide development, using agents that selectively target SEVI. This high-risk/highreward approach is fundamentally different from traditional microbicidal strategies that target the 

virus itself, and is expected to be highly complementary with direct antiviral approaches. Indeed, 

our long-term goal is to use SEVI-targeting agents in combination with traditional microbicides, 

to achieve optimal antiviral effectiveness. In the R21 phase, we will test whether novel amyloidbinding small molecules inhibit semen-mediated enhancement of HIV infection. The feasibility 

of this approach has been established using two amyloid-binding small molecules which contain 

"shielding" oligo-ethylene glycol (EG) moieties: BTA-EG4 and -EG6. These agents efficiently 

inhibit SEVI- and semen-mediated enhancement of HIV infection. In Aim 1, we will generate 

and test novel derivatives of these and other amyloid-binding molecules, including oligovalent 

molecules that are expected to possess increased SEVI binding affinity. We will then test their 

ability to inhibit SEVI- and semen- mediated enhancement of HIV infection using a panel of R5 

virus strains (including different clades and transmitted strains). In Aim 2, we will examine the 

interaction between novel amyloid-binding small molecules and cells from the female 

reproductive tract. We will evaluate whether our compounds are toxic to human cervicovaginal 

epithelial cells (HCEC), and we will test whether they inhibit SEVI-enhanced binding of HIV-1 

to HCEC and/or SEVI-enhanced trans-infection of PBMC by HCEC exposed to HIV-1 virions. 

The R33 phase will be undertaken only if well-defined milestones are achieved. In Aim 3, we 

will use structure-activity relationship (SAR) data to refine our chemical compositions. We will 

also test whether our lead molecules have efficacy in a cervical explant model for HIV-1 

infection, and whether they have a synergistic or additive effect on the ability of other candidate 

microbicides to inhibit HIV-1 infection in the presence of semen. In the final Aim, we will assess 

the toxicity and inflammatory effects of the most promising candidate molecules, using 

beneficial Lactobacillus strains and cervical explants. The R33 phase will culminate with an 

evaluation of the safety and tolerability of the most promising compound in the rabbit vaginal 

irritation (RVI) model. The overall goal of these studies is to carefully determine whether small 

molecules that target SEVI have potential utility as a novel class of microbicides. 
72

1-R21-AI-094514-01

Designing optimal microbicide delivery integrating rheology and acceptability

Hayes, John Edward

Pennsylvania State University

$18,750

Globally, HIV is a heterosexual disease, so there is a strong demand for women initiated and 

controlled prevention options. Microbicides have strong potential to meet this need, but only if 

formulation scientists can make products that effectively prevent HIV transmission while being 

acceptable to users - if products are sticky or messy, women will not use them, even if they work 

in the lab. Here, we incorporate user acceptability early in the optimization process to make 

formulations that maximize drug delivery and user acceptability at the same time, instead of 

considering acceptability only as an afterthought in the formulation process. This year perhaps 

2.5 million people will be added to the approximately 35 million already infected with 

HIV/AIDS, 50% of whom are women. Topical microbicides offer these women a means to 

prevent sexually transmitted infections (STIs), including HIV. However, in addition to concerns 

about the biological efficacy of current microbicides, user acceptance of and adherence to their 

use is suboptimal. It has been estimated that a single microbicide with even limited efficacy 

could prevent millions of new HIV cases annually. The design of vaginal microbicide dosage 

forms has challenged formulation scientists. Safe and efficacious products are necessary, but not 

sufficient to assure adherence. User acceptability depends both on the physical properties of the 

material and behavioral factors. Constraints that drive acceptance must be identified and 

addressed early in development. The acceptability of the product to women must be evaluated 

preclinically. We propose the rational preclinical design and development of a dosage form that 

delivers an immediate efficacious dose of active pharmaceutical ingredient (API) followed by the 

slow release of API over a period of 1-3 days to maintain efficacy. This dosage form can be 

thought of as a temporal vaginal ring/diaphragm that releases API(s) as it slowly erodes away. 

These products will be an adaptation of current softgel capsule technology. However, unlike 

current gelatin capsules, we will develop a range of non-gelatin capsules varying in shape and 

firmness (texture). Human perceptual data will be assessed throughout and guide the design 

process. Carrageenan will be used for the development of heat-stable softgels that, unlike current 

gelatin capsules, will not melt in tropical environments. The two-phase nature of softgels 

('ovules') will permit the inclusion of a second component. Our R21 goals provide for proof-ofconcept of this new delivery system, and the R33 goals will optimize both acceptability and 

biophysical functionality. The R33 will also explore potential higher-order functionality, like 

mucoadhesion or delivery of probiotics. Here, we propose a new microbicide delivery system, 

designed to overcome both biological (insufficient HIV neutralization) and behavioral (poor 

acceptability and adherence) deficiencies of current products. By designing formulations that 

function for optimal efficacy and optimal use (acceptability / adherence), microbicides produced 

via these methods are likely to have a greater impact on the HIV/AIDS pandemic than those 

currently in the development pipeline. Also, by developing a methodology for design of vaginal 

products where multiple factors (shape, texture, size, and multi-stage delivery) play a central 

role, we increase the options women have in microbicide use. Critically, our product type is 

flexible - allowing for multiple textures, sizes, shapes and antiviral strategies - to accommodate a 

range of user preferences. 
73

1-R21-AI-094515-01

Mucosal Tissue Explants As Surrogates For In Vivo Efficacy Of Microbicides

Herrera, Carolina 

St. Georges's, University Of London

$18,750

This project seeks to establish methods to predict in humans the potential of candidate 

microbicides to prevent sexual HIV infection. Currently microbicides are often tested in nonhuman primates (NHPs) to determine if they can prevent vagina or rectal infection with SHIV (a 

monkey equivalent of HIV). However there is no way to determine whether the dose of drugs 

shown to be protective in NHPs would be the same as that required to protect humans. The main 

goal of this project is to test whether biopsies taken from animals or humans treated with 

microbicides are protected from infection when challenged in the laboratory. The series of 

experiments proposed in this study will test whether use of human biopsies have potential for 

predicting the dose of drug required to protect individuals using a microbicide from sexual 

transmission of HIV. The HIV microbicide field is dependent upon testing in non-human 

primates (NHPs) as the only relevant model to study infection. However, the predictive accuracy 

of NHP studies of efficacy in humans has not been validated and as such the economic value is 

unknown. Hence, refinement of this model and development of a novel correlate of efficacy in 

humans that will reduce the potential use of NHPs is key for the global progress of microbicides 

and specifically of the Microbicide Innovation Program's mission. This proposal addresses these 

issues by testing the hypothesis that ex vivo tissue explant cultures can provide a potential 

surrogate of in vivo efficacy through measurement of intra-tissular drug pharmacology and ex 

vivo infection/protection. This will be investigated using combined expertise in modeling 

mucosal tissue infection and measurement of antiretroviral (ARV) drug pharmacokinetics and 

pharmacodynamics in tissue. The proposal will focus on a reverse transcriptase inhibitor, PMPA 

(tenofovir), and an entry inhibitor, maraviroc, used alone and in combination as candidate 

microbicides. In the R21 component of the proposal we will demonstrate the robustness of our ex 

vivo explant models for analysis of pharmacological parameters and ex vivo infection 

independently of the origin (human or NHP) and the type of mucosa (cervicovaginal or 

colorectal). This will be investigated through two Specific Aims: 1) to define ex vivo 

pharmacological dose-responses (pharmacokinetics and pharmacodynamics) in human and 

rhesus macaque mucosal tissue explants; 2) to define whether the viral backbone affects 

pharmacological correlates of activity. The next step of our proposal in the R33 component will 

involve validation of the model as a surrogate for prediction of in vivo efficacy of ARV drugs as 

vaginal and colorectal microbicides. Here the two Specific Aims are: 3) to assess whether 

activity of drugs titrated in vivo can be predicted with ex vivo challenge models: 4) to correlate 

ex vivo and in vivo protection and drug dosing in NHPs. The iterative design of the overall 

proposal will allow us to assess correlates between intra-tissular pharmacological dosing and 

efficacy at all levels: tissue type, origin of tissue, route of dosing and challenge, and nature of 

experiment (ex vivo, in vivo). These correlates will define "conversion factors" of microbicides 

efficacy between the NHP model and in humans, which will be key for the rational development 

of existing and future candidate microbicides. 
74

1-R21-AI-094519-01

Mucus Penetrating Particles for Rectal Microbicides

Hanes, Justin S. 

Johns Hopkins University

$18,750

Rectal transmission of HIV significantly increases the AIDS pandemic. The aim of this project is 

to develop mucus penetrating particles for colorectal drug delivery that will maximize protective 

efficacy and minimize toxic effects of rectal microbicides for protection against HIV and other 

STDs. These novel particles can be delivered in enemas and lubricant gels designed to be highly 

acceptable to potential users since enemas and gels are frequently used for rectal intercourse 

even though they provide no disease protection. For reliable protection against STD 

transmission, rectal microbicides must be formulated in a way that will deliver the active agent to 

all the surfaces that are susceptible to infection. These include the entire rectum as well as a large 

fraction of the colon (due to peristaltic stirring of colonic contents). Colorectal surfaces are 

columnar epithelia that are mechanically and osmotically fragile, and are highly susceptible to 

STD transmission. Although continuous mucus secretion by these susceptible surfaces helps 

protect against trauma and pathogens, this continuously secreted mucus also poses a significant 

barrier against effective delivery of microbicides to the epithelial surface. Recently we developed 

novel mucus penetrating nanoparticles (MPP) that can overcome this barrier and provide 

sustained, well-distributed delivery of drugs to mucosal surfaces. Our hypothesis is that MPP 

will significantly increase the protective efficacy of rectal microbicides by achieving more 

uniform and complete colorectal distribution, sustained drug activity, and thus longer duration 

and more complete protection compared to drug delivered in gels ("free drug") or drug delivered 

in conventional nanoparticles, "CP", that adhere to mucus and fail to penetrate mucus barriers. In 

the R21 phase, we will determine optimal MPP properties for penetration of mouse colorectal 

mucus, and we will characterize the uniformity of MPP distribution and retention times in the 

mouse colorectum compared to CP and free drug. We will then prepare drug-loaded 

biodegradable and biocompatible MPP that provide sustained release of antiviral drugs 

(valacyclovir for HSV and UC-781 for HIV). We will deliver these MPP in both a rectal enema 

format and a rectal lubricant gel format since both formats are frequently used for enhancing 

rectal intercourse. Moreover, an enema may deliver MPP to large regions of the colon unlikely to 

be reached by a gel. The key milestone for the R21 phase will be development of valacyclovirMPP and UC-781- MPP that provide more complete and persistent coverage of the rectal 

epithelial surface, with minimal toxicity, compared to CP formulations or free drug. In the R33 

phase, we will extensively test these MPP formulations for safety and protective efficacy in our 

mouse/HSV rectal model and in the hu-BLT-SCID mouse/HIV model (via a subcontract with Dr. 

J. Victor Garcia-Martinez at UNC). 
75

1-R21-AI-094555-01

Development Of An HIV-1 Entry Inhibitor Pre-Drug As A Microbicide

Lu, Min

University Of Medicine/Dentistry Of New Jersey-NJ Medical School

$18,750

In the absence of an effective vaccine against HIV-1, there is an urgent public health need to find 

alternative approaches, such as vaginally applied microbicide gels, to prevent heterosexual HIV1 transmission. Since blocking HIV-1 entry is the first line of defense against viral infection, the 

HIV-1 envelope glycoprotein is a favored target for microbicide development. Several HIV-1 

fusion and entry inhibitors have been shown to be effective in blocking SHIV transmission in a 

rhesus macaque model. The results of this project will lead to preclinical proof-of-concept for 

optimized fusion-inhibitory peptides as a practical microbicide. With no vaccine in sight, there 

is an urgent public health need to develop an effective topical microbicide that can reduce the 

number of new HIV-1 infections in women. The potential role of virus-cell fusion inhibitorbased microbicides in preventing mucosal transmission of HIV-1 has been clearly identified. 

However, none of the reported gp41 fusion inhibitors has made significant progress toward 

clinical trials. HIV-1 infection requires fusion of the viral and cellular membranes, driven by 

association of two heptad-repeat regions in the gp41 ectodomain to form a highly stable six-helix 

bundle structure. Whereas this postfusion motif comprising native N36 and C34 peptides has no 

inhibitory activity, the isolated peptides inhibit HIV-1 entry by binding to their cognate sites on 

gp41. Our goal in this MIP VI application is to develop an inexpensive, potent, structured 'prodrug' form of the N- and C-peptide fusion inhibitors that exhibits significant microbicidal activity 

upon use in situ. Our development effort will be based on preliminary data obtained with a 

truncated six-helix bundle that inhibits in vitro infection by primary HIV-1 isolates with low 

nanomolar IC50 values. We propose a comprehensive, interdisciplinary approach that combines 

high-resolution structural determination, recombinant protein production and mutagenic 

analyses, virology, and animal model efficacy studies. In this project we seek to conduct in vitro 

and in vivo preclinical and animal model-based research intended to facilitate the development 

of new HIV-1 gp41 peptide fusion inhibitor as a practical microbicide. The Specific Aims are: 1. 

To optimize and identify HIV-1 peptide fusion inhibitors for development as a vaginal 

microbicide. (a) To identify and incorporate specific amino-acid residue substitutions that 

optimize both potency and solubility of fusion inhibitor peptides. (b) To develop and optimize 

robust procedures for the large-scale bacterial expression and purification of select fusion 

inhibitor peptides. (c) Investigate the mechanisms of resistance to peptide inhibitors so as to 

avoid eliciting resistance. 2. To characterize the specificity, potency and toxicity of optimized 

peptide fusion inhibitors and their in vitro synergistic interactions with the CCR5 inhibitor 

CMPD167 and the entry inhibitor BMS-378806. (a) Determine the virucidal activity of 

optimized fusion inhibitor peptides against a diverse set of primary HIV-1 isolates. (b) Evaluate 

their toxicity, immunogenicity and drug stability in the rabbit model. (c) Study antiviral synergy 

in vitro in order to make rational predictions for lead inhibitor combinations for in vivo efficacy 
76

testing. 3. To test the effectiveness of the fusion inhibitor peptides to protect against mucosal 

HIV-1 infection. (a) Characterize the specificity and potency of effective peptide inhibitors in an 

in vitro model of HIV-1 infection of human cervical and vaginal tissue. (b) Use the NOD/SCIDhu BLT mouse vaginal transmission model to assess the in vivo potency and breadth of activity 

of highly effective peptide inhibitors alone and in combination with the small-molecule CCR5 

inhibitor CMPD167 and the small-molecule entry inhibitor BMS-378806. 1 

1-R21-AI-094584-01

Cervical/Vaginal Mucus and Microbicides

Hope, Thomas

Northwestern University

$18,750

To develop a functional microbicide it is critical to know how it will interact within HIV in the 

context of the female genital tract. This is a critical issue as previous clinical trials have indicated 

that microbicides do not function as expected in the presence of semen. Likewise, other factors, 

such as cervical/vaginal mucus, might also modulate microbicide function. To date, little is 

known about how HIV interacts with these fluids and how the interaction of these fluids changes 

the local environment. Even less is known about how microbicides interact with HIV within this 

milieu. For example, the vehicle delivering the microbicide might interact with the biological 

fluids of sexual transmission to either increase or inhibit HIV acquisition or microbicide potency. 

The Hope laboratory has recently developed methods that allow the transport of HIV with 

cervical and cervical/vaginal mucus to be analyzed and quantified. These studies have revealed 

that mucus can perturb HIV transport and is pH sensitive. At acidic pH, as is found in the 

lactobacilli influenced environment of the vaginal vault, HIV transport is greatly reduced. At 

neutral pH, such as when semen is introduced into the system, HIV transport is reduced 10-15 

fold relative to what is observed in media (water). Additionally, we have found, but not yet 

published, that virus-binding antibodies can further reduce transport in neutral pH cervical 

mucus. These antibodies do not need to be neutralizing as any antibody binding to the virus can 

decrease virus transport. Semen also contains mucins and other components that have the 

potential to alter HIV transport as we have observed in cervical mucus. How HIV is transported 

within semen and how this changes when mixed with mucus or microbicides is not defined. How 

this process influences HIV transport and interaction with mucosal barriers is not understood. In 

the first phase (R21) of this proposal we will define how HIV is transported in semen alone and 

mixed with mucus and/or microbicide vehicles such as carbopol gel and hydroxy ethyl cellulose 

(HEC). In the second phase (R33) of this proposal we will extend our studies into the 

environment of the rhesus macaque female genital tract to determine how biological fluids and 

microbicide vehicles alter the way that virus interacts with the mucosal barriers of this 

environment and how these changes can increase or decrease SIV acquisition. These studies will 

lead to a better understanding of how virus interacts with biological fluids and how these 

interactions might alter microbicide efficacy.
77

IMMUNITY/AUTOIMMUNITY

5-U19-AI-082719-03

Autoimmunity Center Of Excellence (ACE) At Stanford 

Fathman, Charles

Stanford University 

$30,000

The Stanford ACE will support an integrated basic and clinical research program focused on 

tolerance induction and immune modulation to prevent or treat autoimmune disease. The major 

theme of the Stanford Autoimmunity Center of Excellence (the Center) is the study of the 

regulation of CD4 T cells in pathogenesis and treatment of autoimmune diseases. The Center 

will support and be supported by other ACE groups across the United States; and will take 

advantage of Stanford's documented leadership in basic and clinical research, technology 

development, and education in clinical immunology. Success of the Center will be supported by 

the interrelationships previously established at Stanford among clinician scientists from multiple 

departments studying autoimmune diseases in multiple organs and tissues. The Stanford ACE 

will be composed of outstanding basic and clinical investigators from multiple disciplines at 

Stanford Medical School and proposes both a basic Research Project, centered on CD4 T cell 

unresponsiveness, and a translational Research Project to study a new T cell lineage (termed 

Th17 cells) that is characterized by the ability of these lymphocytes to secrete high levels of the 

proinflammatory cytokine interleukin-17 (IL-17). Proposed clinical research projects encompass 

three different autoimmune diseases [diffuse systemic sclerosis (SSc), psoriatic arthritis and 

systemic juvenile idiopathic arthritis (SJIA)] that afflict adults and children, as well as organ 

systems including joints, skin, blood elements, and blood vessels, and will both test efficacy of 

therapy and develop tests to characterize the mechanisms of action of these therapeutics. The 

proposed Pilot and Feasibility Project proposes a two year research plan in Systemic Juvenile 

Idiopathic Arthritis (SJIA) patients to identify and validate urine peptide biomarkers that predict 

(a) response to TNF inhibition; (b) response to IL-1 inhibition; and (c) impending disease flare. 

In addition, this proposal will provide other ACE groups access to cutting edge reagents and 

technology platforms for studying human autoimmune diseases, and dissemination of 

Educational Materials that can be used by other ACEs to teach clinical immunology concepts to 

high school, undergraduate, graduate, postgraduate, and clinical fellows and faculty. The 

Stanford ACE proposes to support integrated basic, pre-clinical and clinical research by 

proposing and then conducting basic and translational research into the mechanism of CD4 T cell 

unresponsiveness; two clinical trials that include novel therapies and mechanistic studies of these 

therapies for autoimmune diseases; and a pilot proposal that intends to develop new bi omarkers 

of disease. PROJECT 1A: Clinical Component (Genovese, M) Stanford University Medical 

Center (SUMC) has an extraordinary tradition of medical, translational, and basic science 

research. An outstanding array of resources, faculty, and facilities will be available to support the 

proposed ACE site at Stanford University. This proposal brings together a skilled group of 

translational researchers with a track record of productivity in both laboratory and clinical 
78

research focusing on human autoimmune mediated diseases. Stanford has brought together 

various disciplines to demonstrate both accomplishment and ability to work together with the 

following fields represented: Adult Rheumatology, Dermatology, Pulmonary Medicine, and 

Pediatric Rheumatology. The projects chosen for this submission highlight the significant 

collaborations that exist between Rheumatology (Adult and Pediatric), Dermatology and 

Pulmonary Medicine. Both clinical trials projects explore dermatologic and rheumatologic 

manifestations of diseases such as Psoriatic arthritis and Systemic Sclerosis. Clinical Trial 

Concept 1: The use of an anti- IL-17 mab in the treatment of active Psoriatic Arthritis Primary 

Hypothesis: The proportion of patients achieving the ACR 20 response from Baseline to Week 

14 among active Psoriatic Arthritis (PSA) subjects treated with IL-17 mab is larger than the 

proportion achieving ACR 20 response from Baseline to Week 14 among active PSA subjects 

treated with placebo Objectives: The goal of this study is to determine the safety and efficacy of 

a monoclonal antibody to lnterleukin-17 (IL-17 mab) in the treatment of PsA with active skin 

and joint disease. Clinical Trial Concept 2: The use of CTLA-4lg (abatacept) in subjects with 

diffuse systemic sclerosis Primary hypothesis: Given several lines of evidence supporting the 

role of activated T cells in affected skin, we hypothesize that inhibiting T cell activation may 

lead to significant clinical improvement in skin manifestations in patients with diffuse systemic 

sclerosis (dSSc), and that changes in tissue and blood autoantibody and cytokine profiles will be 

associated with clinical response. Objectives: The primary goal of this study is to determine the 

safety and efficacy of CTLA-4lg (Abatacept) for the treatment of cutaneous manifestations of 

dSSc. The Stanford ACE will support an integrated basic and clinical research program focused 

on tolerance induction and immune modulation to prevent or treat autoimmune (Al) disease. The 

Stanford ACE proposes clinical research projects that encompass three different autoimmune 

diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for 

preventing or treating different Al diseases.

5-U19-AI-082714-03

Oklahoma Autoimmunity Center Of Excellence

James, Judith 

Oklahoma Medical Res Foundation 

$30,000

The Oklahoma Medical Research Foundation is home to outstanding clinical and basic science 

investigators who have research interests in the etiology and pathogenesis of autoimmune 

diseases and seek to identify novel therapeutics for more effective patient treatments. The 

scientific expertise, extensive clinical trial experience, access to geographically distinct patient 

populations, as well as unique patient registries, repositories and core technologies provide a 

solid foundation for the Oklahoma Autoimmunity Center of Excellence (ACE) application to 

which we have added a multidisciplinary team of clinical and basic science investigators. The 

focus of the Oklahoma ACE application is on expediting the translation of scientific discoveries 

in autoimmunity to clinical application in the diagnosis and treatment of systemic autoimmune 

diseases. To accomplish this, the Oklahoma ACE comprises two research projects, a proposed 

pilot research project, a Clinical Center (Joan Merrill, PI) and an administrative core (Judith 

James, PI). The research projects focus on thrombotic thrombocytopenic purpura, systemic lupus 

erythematosus, and Sj"gren's syndrome, which are also focuses of the Clinical Center. Multiple 
79

sclerosis, rheumatoid arthritis, pediatric arthritis, insulin-dependent diabetes, idiopathic 

thrombocytopenia and pediatric lupus are other key disease emphases of the Clinical Center. 

Two complimentary, but unique, research projects focus on understanding early events in the 

development of lupus autoimmunity and in defining targetable genetic associations in Sj"gren's 

syndrome. The pilot project uses complimentary methods to address roles of elevated interferon 

activity in patients with TTP and a novel animal model of thrombocytopenia. In addition, two 

clinical trials are proposed; both of which enhance or build upon the basic science projects. The 

first studies efficacy and mechanistic affects of anti-IFN in select SLE patient subsets by 

applying a patient centric, dose optimization strategy. The second tests the efficacy and early 

MRI changes of a novel MEK1/MEK2 inhibitor in RA with additional mechanistic studies. The 

Administrative Core will provide leadership and management through acting on behalf of the 

Oklahoma ACE members within the ACE Network and NIH Program, ensuring fiscal 

responsibility for the ACE, and providing an educational foundation for a multi-disciplinary 

approach to autoimmune disease research. Thus, the Oklahoma ACE will unite Oklahoma-based 

clinical and basic science experts to facilitate access to unique patient populations for 

participation in clinical trials and to understand basic mechanisms of etiology and pathogenesis. 

The Oklahoma ACE brings together adult and pediatric rheumatologists, neurologists, 

endocrinologists, dermatologists, hematologists, dentists, ophthalmologists, geneticists, 

immunologists, molecular biologists, epidemiologists and biostatisticians to provide a 

multidisciplinary approach to discovering and applying novel therapeutics in systemic 

autoimmune diseases. Through strong basic science projects paired with clinical expertise the 

Oklahoma ACE will provide unique research and clinical opportunities to the ACE Network. 

The Oklahoma ACE Clinical Center brings together disease-specific and interdisciplinary clinics 

in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj"gren's syndrome, 

thrombotic thrombocytopenic purpura, insulin dependent diabetes mellitus, pediatric SLE and 

juvenile inflammatory arthritis to forward translational research in autoimmunity. Patients from 

each of these disease populations are available and committed to participate in potential national 

ACE investigations. With adult and pediatric rheumatologists, adult and pediatric 

endocrinologists, neurologists, hematologists, dermatologists, ophthalmologists and dentists, as 

well as basic scientists from various areas of immunology, molecular biology, genetics, 

epidemiology and biostatistics, our investigative team is poised to make basic advances 

regarding disease pathogenesis and to help translate these discoveries to the clinic. The Clinical 

Pharmacology program at OMRF will serve as the primary home for the SLE, RA, Sj"gren's 

syndrome and TTP clinics. Currently leading or participating in more than 20 active clinical 

trials, this clinical center is accustomed to participating in clinical trials, managing confidential 

patient information, and providing multidisciplinary care. In addition, the Clinical Pharmacology 

space provides investigators access to state-of-the-art research tools directly adjacent to the 

patient care unit. Pediatric IDDM and rheumatology clinics are housed across the street at 

OUHSC and a large, community based multiple sclerosis clinic will participate for MS patient 

investigation. Joan Merrill, MD serves as the leader of our Clinical Center. She is the current 

medical director of the Lupus Foundation of America and a leader in SLE clinical trial 

development. She has served as the lead investigator on large, multi-site trials. Combining her 

extensive knowledge of clinical trial design and the known heterogenic presentation of SLE, she 

proposes to devise patient-centric clinical trials that use biomarkers of disease to optimize 

therapeutic doses. Our Clinical Center proposes two potential clinical concepts. Based upon our 
80

basic science investigation regarding pivotal roles for increased interferon activity in pre-clinical 

SLE, Sj"gren's syndrome and potentially TTP, our first trial examines the efficacy and biologic 

impact of anti-INF alpha in SLE patients with arthritis and select dermatologic manifestations. 

The second trial proposes use of a first-in-class target of MEK1/MEK2 inhibition in RA to assess 

impact on MRI progression of disease and on select biomarkers. Both of these trials have 

mechanistic studies proposed to address key scientific questions regarding pathogenesis and 

response. The Oklahoma Autoimmunity Center of Excellence Clinical Center will provide 

interdisciplinary investigators with unique populations of well-characterized patients to 

participate in ACE network autoimmune disease clinical trials. With our rich Native American 

heritage and large rural populations, the patients provided by the Oklahoma ACE will be 

previously understudied and provide unique insights for therapeutic trials.

5-U19-AI-082715-03

A Systems Biology Approach For Pediatric And Adult Autoimmune Diseases - ACE

Pascual, Maria Virginia 

Baylor Research Institute

$30,000

We propose to create an Autoimmunity Center of Excellence that will incorporate the efforts of 

clinicians, human immunologists (both basic and translational), physician-scientists with clinical 

expertise and research experience in autoimmunity, bioinformaticians, and geriomics/systems 

biologists. Together, the assembled group has an extensive background in clinical trials and a 

proven track record for merging basic and clinical science. This team is committed to bringing 

innovative treatments from the laboratory bench to their patients' bedside. Within this 

collaborative setting, a systems biology approach is proposed to focus on both pediatric and adult 

autoimmune diseases. The goals of the Center are: 1) To assess the efficacy of novel targeted 

therapies, 2) To develop simple and robust biomarkers using state-of-the-art genomic 

approaches, 3) To understand the role of recently identified T cell subsets in disease 

pathogenesis, and 4) To assess antigen-specific responses in pediatric and adult autoimmune 

diseases. These projects will provide a better understanding of the pathogenesis of specific 

autoimmune diseases and allow us to develop a strategy to assess disease activity based on novel 

transcriptional markers as well as to identify autoantigen-specific immune responses. The Center 

will deliver: 1) Innovative clinical trials targeting specific cytokines in psoriasis & 

dermatomyositis. 2) Development of biomarkers for dermatomyositis, psoriasis, lupus and 

multiple sclerosis. 3) Identification of novel therapeutic targets in dermatomyositis. 4) 

Development of assays to test autoantigen-specific immune responses. 5) Development of a 

unique microarray database of human autoimmune diseases. Clinical Component (Cush, J): 

Baylor Institute for Immunology Research aims to bring together a distinguished team of clinical 

investigators to conduct cutting-edge clinical trials on specific autoimmune diseases. This unique 

group of investigators and clinicians has appointments at Baylor University Medical Center, UT 

Southwestern Medical Center, Texas Scottish Rite Hospital in Dallas and Northwestern 

University. These talented individuals have been enlisted from diverse programs with 

subspecialties in dermatology, rheumatology, neurology, pediatrics, and human immunology. 

They provide a set of inimitable resources for clinical trials and have a proven track record for 

merging basic and clinical science. Indeed, this team is committed to bringing innovative 
81

treatments from the laboratory bench to their patients' bedside. With such outstanding 

collaborative players, a systems biology approach is proposed here which investigates both 

pediatric and adult autoimmune disease. To this end, two Phase II randomized, double-blind, 

placebo-phase controlled clinical trials are proposed. The first trial investigates whether blocking 

IL-1 with Anakinra will result in objective disease improvement for patients with Juvenile 

Dermatomysitis. The trial design will demonstrate: 1) if the time to improvement for patients 

receiving Anakinra early in the study will be earlier than those who receive later treatment; and 

2) if the proportion of patients improved at week 8 of the blinded phase will be significantly 

greater in the early treatment group. Mechanistic studies will utilize gene expression profiling 

assays to find a novel diagnostic test for JDM as well as disease activity measures and 

biomarkers to follow and predict patients' response to therapy. The second clinical project 

proposes to use a-IL-17 in patients with plaque psoriasis as well as psoriatic arthritis. 

Specifically, this study will assess the safety and efficacy of a-IL-17 in these patients and 

determine both the time to achieve endpoints of a PASI 75 or ACR20 and sustainability of such 

responses at 24 weeks. Associated studies will establish blood transcriptional markers to predict 

clinical responses in patients treated with a-IL-17, determine if transcriptional scores can be used 

to assess disease activity, and analyze the effect(s) of IL-17 blockade on B and T cell subsets. A 

dynamic team of clinical investigators assembled at BUR to conduct state-of-the-art clinical 

trials on autoimmune disease would be of great value and accelerate the process of bringing 

research from the laboratory bench to the bedside. This team proposes two important trials that 

will assess a-IL-1 treatment in Juvenile Dermatomyositis and IL-17 blockade in psoriatic 

diseases.

5-U19-AI-056363-08

Mechanisms Of Beta Cell Responses In Autoimmune Disease - ACE

St Clair, Eugene William 

Duke University

$30,000

This application is a competitive renewal of the Autoimmunity Center of Excellence (ACE) at 

Duke. Its research focus will continue to be modulation of B cell responses in autoimmune 

disease. The ACE will be under the leadership of Dr. E. William St. Clair, Professor of Medicine 

and Immunology. For the past 5 years, Duke has been a productive member of the ACE network, 

contributing new insights into the developmental pathways of B cells and the mechanisms of B 

cell directed therapy. The proposed ACE builds on these discoveries and will support 2 new 

basic science projects, 5 ongoing and 2 new clinical trials, and an Administrative Core, and 

continue to emphasize a strong and fluid integration between the bench and the bedside. Tedder 

and colleagues have recently found that a phenotypically unqiue subset of B cells secreting IL-10 

(called B10 cells) serve as critical negative regulators during adaptive CD4+ T cells responses, 

and dramatically suppress Th1 immune responses and autoimmune disease in mice. For Basic 

Research Project 1, they will examine the hypothesis that antigen-specific regulatory B10 cells 

modulate autoimmune responses in mice and man and that they can be manipulated for 

therapeutic gain. A picture is gradually emerging about the precursors of self-reactive B cells in 

autoimmune disease. Kelsoe and coworkers in Basic Research Project 2 will investigate 

developmentally regulated expression of activated cytidine deaminase (AID) in human fetal and 
82

neonatal pre-, pro, and immature/transitional B cells and its relationship to the generation of selfreactive B cells in human autoimmune disease, potentially eludidating another pathway of B cell 

self-reactivity outside the confines of normal tolerance mechanisms. We propose two new 

clinical trials to investigate lymphotoxin-beta receptor fusion protein as a treatment for primary 

Sj"gren's syndrome, and rituximab therapy for bullous pemphigoid. A Pilot Research Project is 

also proposed to engineer tetramers of self-antigen enabling the identification and 

characterization of self-reactive B cells, which will have implications for the goals of the clinical 

and other basic research projects. Overall, the Duke ACE will bridge these basic and clinical 

studies to advance our understanding of autoimmune disease. The B cell is a type of immune cell 

essential to autoimmunity. The goal of the proposed Autoimmunity Center of Excellence at Duke 

is to improve our understanding of the roles played by B cells in human autoimmune disease. 

The projects are designed to be highly integrative between the bench and the bedside, with 

collaborations between basic and clinical scientists. These studies may lead to better treatments. 

Clinical Component (ST CLAIR, W): The Clinical Research Component of the Autoimmunity 

Center of Excellence shares with the Basic Research omponent an overall goal of advancing our 

understanding about the role of B cells in the pathogenesis of autoimmune diseases. This 

component will be directed by Dr. E. William St. Clair. During the past 5 years, the Duke ACE 

has brought 3 new clinical trial concepts to the ACE Steering Committee, resulting in 1 

completed trial, 1 ongoing trial, and 1 protocol in development. We are also participating in 3 

other ongoing ACE-sponsored clinical trials. Therefore, substantial clinical research activity will 

carry over to the next funding cycle. Our center is organized to support clinical trials in 

rheumatology, dermatology, gastroenterology, hematology, and neurology. We have access to 

several large patient populations, including patiens with rheumatoid arthritis, systemic lupus 

erythematosus, primary Sj"gren's syndrome, scleroderma, autoimmune blistering disease, 

psoriasis, inflammatory bowel disease, autoimmune hepatitis, anti-phospholipid antibody 

syndrome, and myasthenia gravis. Each of these disease areas has leadership from one or more 

physician-investigators with significant clinical trial experience, including an example of a 

productive inter-institutional collaboration. The physician leadership is supported by an ample

infrastructure that provides clinical research space, infusion facilities, experienced clinical 

coordinators, and an Immune Monitoring Component. The Clinical Research Component aligns 

with the ACE at a thematic level, with substantial collaborations between basic and clinical 

scientists. To this end, the proposed clinical trial concepts will focus on B cell directed therapy. 

In one case, we propose to examine the clinical efficacy of lymphtoxin-beta receptor fusion 

protein in the treatment of primary Sj"gren's syndrome, and have already secured commitment 

from the industry sponsor to provide study drug for this trial. The other application will 

investigate rituximab as initial therapy for bullous pemphigoid. The mechanistic studies for these 

proposed trials as well as current trials are highly integrated with the basic research projects. The 

Clinical Research Component will make a significant contribution to the ACE enterprise during 

the upcoming funding cycle. The Clinical Research Component will support clinical trials 

sponsored by the Autoimmunity Centers of Excellence in several disease areas, including 

rheumatology, dermatology, gastroenterology, hematology, and neurology. It has been 

productive during the current funding cycle, and has the capability, as shown in this application, 

to generate new ideas for clinical trials that can be translated into well-designed studies.
83

5-R21-AI-090344-02

Sex Differences in Protective Immunity Against Influenza A Viruses

Klein, Sabra

Johns Hopkins University

$243,540

Sex differences in the incidence and severity of influenza A virus infection as well as in response 

to vaccination have been documented in humans. Small animal models are critical for 

establishing the mechanisms mediating why males and females respond differently to influenza 

virus infection and vaccination. They will evaluate whether higher humoral immune responses 

following sublethal infection confers greater protection from challenge with pathogenic influenza 

A viruses in females compared with males and the extent to which these differences are mediated 

sex steroids, which may provide clues into why responses to pandemic influenza A viruses differ 

between the sexes and during pregnancy. Sex differences in the incidence and severity of 

influenza A virus infection have been documented in humans. Although exposure rates are often 

higher in men, fatality following exposure to pathogenic influenza A viruses is reportedly higher 

in women. Sex differences also are reported in response to influenza virus vaccines, with women 

consistently mounting higher antibody responses and developing more frequent and severe side 

effects following vaccination than men. Small animal models are critical for establishing the 

mechanisms mediating why males and females respond differently to influenza virus infection 

and vaccination. Following primary inoculation with the mouse-adapted influenza A viruses 

A/PR/8/34 (PR8; H1N1) or A/HK/68 (HK68; H3N2), female mice mount higher inflammatory 

and humoral immune responses than males. Their preliminary data further reveal that elevated 

immunity in females against influenza A viruses represents a delicate balance between immune 

responses conferring protection or causing pathology. The goal of this proposal is to develop a 

small animal model to test the hypothesis that protective immunity to heterosubtypic influenza A 

virus challenge differs between the sexes and is modulated by sex steroid hormones. In Specific 

Aim 1, they will establish whether neutralizing antibody responses, virus-specific T cell 

responses, and protection against lethal influenza A virus challenge is greater among females 

than males. Whether males and females differentially rely on subsets of adaptive immune cells 

for protection against lethal influenza A virus infection has not been documented; thus, they also 

propose to compare heterosubtypic immune responses between male and female mice devoid of 

specific adaptive immune cell populations. If protective heterosubtypic immunity is elevated in 

females compared with males, then estrogens and/or progestins may enhance and androgens may 

suppress adaptive immunity against heterosubtypic influenza A virus challenge. In Specific Aim 

2 they will test this hypothesis by manipulating sex steroid concentrations in vivo and 

establishing the effects on humoral and cell-mediated immunity as well as protection from lethal 

influenza A virus challenge. These are a series of high risk-high return experiments because 

there are no data to date assessing the sex-specific induction of heterosubtypic immunity in 

response to influenza A virus infection. Demonstrating that females mount a broadly protective 

immune response, however, will have important implications for dealing with annual epidemics 

of influenza, as this may explain why the attack rates for influenza are higher in men than in 

woman and influenced by pregnancy. 
84

5-R21-AG-034523-02

Exploring Factors Influencing Gender Disparities in Access To Transplantation

Segev, Dorry

Johns Hopkins University

$205,000

Although kidney transplantation is safe, effective, and life-extending for many patients, women 

have significantly less access to transplantation than their male counterparts, and they have 

shown that this disparity is widest among older women compared with older men. It is unknown 

whether this happens because of patient-level barriers to seeking transplantation or because of 

provider-level biases against referral of women compared with men. Since over 50% of dialysis 

patients are over the age of 65, equal access to transplantation for this subgroup is important; the 

goal of this project is to explore potential sources of the gender disparity in access to 

transplantation, and access to healthcare in general, so that interventions to minimize this 

disparity can be designed. In the modern era, kidney transplantation is a safe and effective 

treatment for many patients with kidney failure. However, choosing the right patients for kidney 

transplantation is difficult, especially among older patients. Although older patients who receive 

transplants survive longer than if they had stayed on dialysis, still very few older patients are 

placed on the transplant waiting list. This is because no tools exist for determining risk in older 

patients undergoing transplantation, so clinical decision making has to be based on subjective 

perceptions of a patient's strength and reserve. Misclassification of these factors by the patient or 

provider likely results in decreased access to transplantation in a population that stands to greatly 

benefit from this treatment. Although transplant outcomes and survival benefit are similar in men 

and women, it has been well established that women have significantly less access to 

transplantation than men. They recently showed that this disparity is strongest in older patients, 

with older women having 30-60% less access than their male counterparts. However, it remains 

unclear whether patient or provider level factors contribute to this disparity. In this study they 

will explore differences by gender and age in factors influencing a patient's decision and ability 

to pursue transplantation. They will then use a new technique to explore the potential role of 

gender and age biases in a provider's choice to refer a patient for transplantation. Understanding 

the root causes of this gender/age disparity is crucial to developing interventions to improve 

access to transplantation, and healthcare in general, for women and older adults. 

1-R21-NS-076200-01

p38 MAPK As A Female-Specific Drugable Target In CNS Autoimmune Disease

Teuscher, Cory

University Of Vermont & St Agric College

$ (NINDS funded this ANSWHR award) 

The objective of this proposal is to explore a new molecular pathway which is likely to be 

important in the pathogenesis of multiple sclerosis (MS), and understanding of this pathway can 

yield new therapeutic targets for treatment of this devastating disease. Further, this proposal 

explores the bases for sexual dimorphisms in efficacy of drug treatment in autoimmune disease. 

This point is highly salient today given the increasing female incidence of MS. Multiple 

sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) 
85

characterized by myelin loss, varying degrees of axonal damage, and progressive neurological 

dysfunction. MS is the most common disabling neurologic disease of young adults and 

adolescents affecting ~350,000 individuals in the United States and more than 1 million 

individuals worldwide. Current MS disease-modifying therapies (DMTs) have limited efficacy

and untoward toxicities, underscoring the need for new approaches based on targeting underlying 

disease mechanisms. The p38 mitogen-activated kinase (MAPK) is a central molecule in 

autoimmune/inflammatory responses in diseases such as rheumatoid arthritis (RA) and Crohn's 

disease, and inhibition of p38 MAPK is currently being explored clinically as a DMT for these 

diseases. However, the role of p38 MAPK in the pathophysiology of MS (or MS models) and its 

potential as a therapeutic target has not been investigated. Using experimental allergic 

encephalomyelitis (EAE), the principal autoimmune model of MS, we tested whether inhibition 

of p38 MAPK can influence EAE susceptibility and disease progression. Treatment of female 

mice with the pharmacological p38 MAPK inhibitor, SB203580, either completely prevented 

disease or halted disease if administered at the onset of clinical signs. Strikingly, male mice were 

completely unresponsive to treatment. These findings suggest that sex-specific factors contribute 

to SB203580 mediated inhibition of p38 MAPK activity and EAE susceptibility. In this 

application, we propose to: 1) determine the molecular and cellular mechanisms targeted by p38 

MAPK inhibition in EAE and 2) determine the basis of the sexual dimorphism in the therapeutic 

response to SB. Understanding the mechanisms of drug action is likely to provide novel, more 

specific drug targets for MS therapy. The gender dichotomy with regard to efficacy of SB203580 

is particularly important, since many autoimmune diseases, including MS, exhibit a femalespecific sexual dimorphism in disease susceptibility. The finding that SB203580 is fully capable 

of selectively inhibiting disease in females provides for the possibility of a unique DMT that 

selectively targets the increasing female MS patient population. No study to our knowledge has 

evaluated the DMT potential of inhibiting p38 MAPK in MS, despite the fact that many 

compounds targeting this pathway are already approved for phase 2 clinical trials in other 

autoimmune diseases. Further, relatively few studies focus on the basis of sex differences in 

therapeutic responses in MS or its models. Inhibition of the p38 MAPK pathway may not only 

provide a novel DMT which selectively targets the increasing female MS patient population, but 

also will likely provide mechanistic insight relevant to development of additional DMTs for MS, 

by uncovering new targets for therapeutic intervention. 

MENOPAUSE

5-R21-AG-037832-02

Ovarian Hormone-Independent Sex Chromosome Effects in Menopause

Ji, Hong

Georgetown University

$153,500

This project is designed to make new discoveries into why postmenopausal women are at 

increased risk for diseases like metabolic syndrome, hypertension and cardiovascular disease 

compared to premenopausal women. They will make these new discoveries by studying sex 
86

chromosome effects independently of the ovarian hormones using a unique animal model in 

which they can separate, for the first time, sex chromosome differences between males (XY) and 

females (XX) from the sex hormone differences (e.g., differences in estrogen and testosterone 

levels). By discovering new genes and pathways responsible for the increased incidence of these 

diseases in ovarian deficient females, new therapeutic treatments are likely to ensue for postmenopausal women and women with ovarian hormone deficiency. Postmenopausal women have 

a higher incidence of diseases such as metabolic syndrome, cardiovascular and renal disease than 

premenopausal women. To begin to uncover genes and pathways that contribute to these adverse 

effects of aging in the postmenopausal woman, they propose two distinct strategies for 

discovering novel genes and pathways that may contribute to the increased risk postmenopausal 

women face towards these diseases. They will take advantage of the "four core genotypes" 

mouse model in which sex chromosome effects can be separated from the gonadal sex thus 

enabling comparisons among XX and XY animals independently of whether they were born with 

ovaries (e.g., XX- vs. XY-females) or testes (XX- vs. XY-males). While recent microarray 

studies in mice have demonstrated that thousands of genes are regulated by gonadal hormones, 

the number of genes regulated by the sex chromosome complement independently of the gonadal 

hormones is far more limited. Thus, they expect to discover a handful of genes (<10) that are 

differentially regulated by the sex chromosome complement (SCC) in the ovarian hormone 

deficient female during over activity of the renin angiotensin system (RAS). Aim 1 will use a 

tightly focused microarray approach leveraging their ability to differentiate SCC from gonadal 

sex to identify genes in the kidney that are differentially regulated by the SCC in the Ang II 

infused E2-deficient female. Aim 2 will use a candidate gene approach to test the hypothesis 

that the regulation of the tissue-specific renin angiotensin system (RAS) in the kidney by 

ovariectomy and hypertension is sex chromosome dependent. They hypothesize that the 

interaction between the XX SCC with the E2-deficient state of ovariectomy tips the 

vasoconstrictor/vasodilator balance of the renal RAS towards vasoconstriction to a greater extent 

than in the XY-Female by increasing plasma and renal levels of Ang II, the ratio of the Ang II 

synthetic enzyme, angiotensin converting enzyme (ACE) to the catabolic enzyme, angiotensin 

converting enzyme 2 (ACE2) and the ratio of the type 1 angiotensin receptor (AT1R) to the 

vasodilator type 2 angiotensin receptor (AT2R). 

1-R21-AG-040568-01

Metabolic Syndrome as Women Undergo the Menopausal Transition: A Multi-Ethnic 

Study

Lee, Jennifer Shuwen

University Of California Davis

$195,983

The Metabolic Syndrome (MetS) is the major predictor for both CVD and type 2 diabetes, and 

can manifest as having one of several constellations of at least 3 of 5 risk components, such as 

high blood pressure and large waist girth. MetS occurs more often in women undergoing the 

menopausal transition, a key 5- to 10-year biological stage in a woman's lifespan. This study 

seeks to enhance significantly our understanding of how women in their 40s and early 50s, over 

time, develop MetS and hormonal changes and other factors during the menopausal transition 

that contribute to their increased risk of MetS. With this better understanding, we intend to 
87

ultimately prevent MetS in women who are high risk due to identifiable and modifiable 

characteristics of their transition to post-menopause. This potentially impacts tens of millions of 

midlife women and their families who face a nearly 1 in 3 chance of developing MetS in their 

remaining lifetime. Young women have much lower rates of cardiovascular disease (CVD, 

including stroke) than men. However, as midlife women transition to post-menopause, they lose 

this 'cardiovascular protection,' and CVD is most common in post-menopause than any other 

stage of a woman's lifespan. Metabolic Syndrome (MetS) is a clustering of 5 metabolic 

abnormalities and is a major predictor of CVD and type 2 diabetes. MetS is clinically diagnosed 

as having any, and at least, 3 of the 5 components. MetS occurrence increases during the 

menopausal transition (MT). Reasons for this are unclear; however this may be due to androgen 

excess, relative to estrogen, during the MT. The proposal's goal is to establish basic aspects of 

how the constellations of the MetS components evolve during the course of the MT, a key 5- to 

10-year biological stage in a woman's lifespan. In turn, this is intended to identify customized 

ways of preventing MetS early and related CVD and diabetes, with effective intervention 

strategies during the MT. The proposal incorporates a shift in our thinking of menopause and sex 

hormones in midlife women, namely, that the increase in MetS occurrence may be due more to 

androgen gain (and less to estrogen loss), in the MT. Our starting hypothesis is that mapping the 

constellations of MetS components, and the number of MetS components satisfied, in the midlife 

will provide a window into bridging the MT, its changing sex hormones, and loss of CV 

protection in women. If correct, this would shift our clinical focus to individualize hormone 

strategies against characteristic MetS constellations and related CVD and diabetes in midlife and 

early post-menopausal women. Aim 1. To characterize the constellations of MetS components 

satisfied over time in women, of 5 race/ethnicities, who develop MetS as they undergo the MT. 

Aim 2. To determine the hormonal and inflammatory factors that predict the course of MetS 

constellations in midlife women as they undergo the MT. We propose an efficient study that 

analyzes unique, existing longitudinal data from the largest U.S. study of the MT, the Study of 

Women Across the Nation (SWAN), a multi-ethnic cohort of 3302 women. Our long-term 

objective is to prevent the dramatic increase in CVD in older women by implementing, in 

midlife, individualized preventative strategies. Both our aims bear directly on this wider 

objective. These would impact 60+ million midlife and older U.S. women. 

5-U01-AG-012531-18

SWAN: Study of Women's Health Across The Nation

Finkelstein, Joel S 

Massachusetts General Hospital

$75,000

The Study of Women's Health Across the Nation (SWAN) is a multi-center, multi-ethnic 

longitudinal study designed to characterize the physiological and psychosocial changes that 

occur during the menopausal transition and to observe their effects on subsequent health and risk 

factors for age-related diseases. The goals of the original RFA were to answer the following 

questions: How do hormones change with the menopausal transition? What factors affect the 

timing of the transition? What are the symptoms that accompany menopause and who is at risk? 

How do cardiovascular risk factors change with the transition and is there ethnic variation? What 

are the rates of bone loss with the transition? When does bone loss begin and what are the risk 
88

factors? What are the health consequences of menopause and who is at risk? SWAN is compiling 

the most comprehensive characterization to date of the health and the physiologic and 

psychosocial changes of women from pre- to postmenopause in community based samples. 

SWAN is now poised to study the effects of these menopause-related changes on subsequent 

healthy aging and on age-related diseases in the post-reproductive period. SWAN I was first 

funded in September 1994 by the National Institute on Aging (NIA), the National Institute of 

Nursing Research (NINR), and the Office of Research on Women's Health (ORWH) in response 

to RFA AG-94-002, Menopause and Health in Aging Women. The first competing continuation 

of SWAN (SWAN II) was funded in 1999 and the second (SWAN III) in 2004. SWAN I, II and 

III have been supported by a cooperative agreement mechanism, with 9 funded components: 7 

clinical centers, a central reproductive hormone laboratory (CLASS), and a coordinating center. 

A second central laboratory (MRL) was originally funded as a subcontract to the Coordinating 

Center (CC). In addition, a Core Repository of serum, plasma, and urine specimens and a DNA 

Repository were established in June 2000 under separate funding (U01 AG 17719, PI: Dr. 

MaryFran Sowers). For non-study-related reasons, site operations at New Jersey Medical School 

stopped in April 2004. The basis of this action was allegations made by two study employees 

who resigned abruptly. The SWAN PI and study coordinator were subsequently exonerated from 

these allegations. Please see Appendix 12 for a more complete report. The grant was transferred 

to the Albert Einstein College of Medicine in 2005. Since that time, the New Jersey PI and 

project director have worked tirelessly to overcome the obstacles to re-implement the study. As 

of June 1, 2008, a total of 155 women have successfully completed their clinic visit and five 

more visits are scheduled. They project that by the end of SWAN III, data will be available for 

250 women. This has been very encouraging and thus Nanette Santoro, PI of the New Jersey 

SWAN site has been approved by the NIA to prepare a U01 application to cover further contacts 

for the Hispanic women. Please note that the SWAN IVproject applications pertain to the 

remaining six sites only. Information relative to the New Jersey site is covered in the separate 

application submitted by Dr. Nanette Santoro. From over 16,000 women aged 40-55 years who 

were screened during 1995-1997, 3302 women aged 42-52 years were enrolled in SWAN's 

longitudinal cohort (approximately 450 at each of 7 clinical centers). They completed their 

baseline clinic visit during 1996-1997. Of the 3302 women enrolled, 1550 were Caucasian, 935 

African American, 286 Hispanic, 250 Chinese, and 281 Japanese. A subset of 880 menstruating 

women was enrolled in the Daily Hormone Study (DHS) started in 1997, which is designed to 

examine cyclical daily hormone and symptom patterns during the menopausal transition.

5-U01-AG-012553-17

SWAN: Study of Women’s Health Across the Nation III

Tyrrell, Kim Sutton

University of Pittsburgh

$125,000

Study of Women's Health Across the Nation (SWAN) has compiled the most comprehensive 

characterization to date of the health and the physiologic and psychosocial changes of women 

from pre- to postmenopause in community based samples. Of particular public health importance 

is that the continuation of SWAN will permit the study to increase understanding of the effects of 

these menopause-related changes on subsequent health and risk factors for age-related diseases. 
89

The SWAN is a 7-center multi-ethnic longitudinal study designed to characterize the 

physiological and psychosocial changes that occur during the menopausal transition. SWAN has 

amassed ten years of data about endocrinology of the transition and other factors relevant to 

midlife health and aging. As SWAN requests its fourth competing renewal, the study itself 

proposes to transition from a study of the menopause to a study of aging in women. The average 

age of participants at the beginning of the SWAN IV project will be 59 years (54 to 65) and 

SWAN IV will follow these women through the age range of 59 to 70. SWAN has the 

unprecedented capability to link the expansive biological, medical, social, behavioral, and 

demographic data it has collected during mid-life and the menopausal transition to the 

development of both positive and adverse health states in early oldage. The primary objectives of 

SWAN IV are to: 1) Characterize the endocrinology and symptomotology of the post-menopause 

(2 to 12 years after final menses); 2) Ascertain additional health outcomes (such as measured 

physical performance) that are relevant to the early old age range and that may be affected by the 

factors that they have studied in mid-life and 3) Understand the relations between the mid-life 

and menopausal transition experience of women and subsequent positive and negative health 

outcomes. To accomplish this, the investigators propose annual phone contact to closely track 

menopausal status, menopausal symptoms and selected health events. In addition, two in-person 

clinic visits are proposed to accomplish detailed physical measures of early disease. The major 

thematic areas of SWAN IV include 1) Physical Functioning; 2) Bone/Osteoporosis; 3) 

Cognitive Function/ Symptoms/ Mental Health and 4) Cardiovascular. New areas for SWAN 

include physical performance and osteoarthritis, history of major depression, and carotid wall 

thickness. SWAN will continue to monitor symptoms, cognition, cardiovascular risk factors, 

endocrinology, bone density and fractures. SWAN IV will advance their understanding of how 

modifiable risk factors related to the menopause transition are linked to sub-clinical disease 

measures and hard outcomes. This may lead to improved strategies for the primary prevention of 

disease in women. 

5-U01-AG-032699-04

Ultra-Low-Dose Estrogen Gel for Vasomotor Symptoms In Women Failing Placebo Or A 

Behavioral Intervention: A Randomized Trial

Lacroix, Andrea

Fred Hutchinson Cancer Research Center (FHCRC)

$200,000

The long-term objective of NIA's RFA-AG-08-004 entitled, "New Interventions for Menopausal 

Symptoms (U01) is to accelerate progress in identifying effective remedies for vasomotor 

symptoms (VMS) in women going through the menopausal transition. They have created a 

network of scientists who are highly knowledgeable about the menopausal transition and 

experienced in the conduct of women's health trials to fulfill this mission. This Data 

Coordinating Center (DCC) application is being submitted in conjunction with the network 

entitled, "The Menopausal Symptoms Initiative-Finding Lasting Answers to Sweats and Hot 

Flashes (MSI-FLASH)". Their DCC will be jointly led by Andrea LaCroix and Garnet Anderson 

who have served together as Co-Principal Investigators of the Women's Health Initiative Clinical 

Coordinating Center (Seattle) for more than a decade. The MSI-FLASH network has five clinical 

sites located in Boston (Lee Cohen and Hadine Joffe, PIs), Indianapolis, IN (Janet Carpenter, PI), 
90

Oakland, CA (Barbara Sternfeld and Bette Caan, PIs), Philadelphia (Ellen Freeman, PI) and 

Seattle (Katherine Newton and Susan Reed, PIs). This multidisciplinary investigator group 

proposes five randomized controlled trials testing a range of behavioral, mind-body, hormonal 

and pharmacologic interventions to treat hot flashes. The specific objectives of the DCC are to: 

1) Provide and coordinate all necessary leadership activities to facilitate collaboration and 

productivity among network scientists during all phases in the lifecycle of VMS clinical trials 

from hypothesis formulation to publication, dissemination, and data sharing; 2) Build upon 15 

years of experience and well established human and operational resources to coordinate 5 or 

more multi- site randomized trials including support of protocol development, recruitment, 

intervention, data collection and management, and statistical analysis; and 3) Create the 

infrastructure to involve an expanded network of scientists from the US and worldwide to 

facilitate the development and use of common methodologies and measurements for VMS trials 

inside and outside of this trial network so that emerging new treatments for hot flashes can be 

rapidly identified and rigorously tested for efficacy and safety with comparable results.

5-R21-NS066147-02

Effects Of Estrogen On Brain Morphology And Neuronal Integrity in Early Menopause

Kantarci, Kejal

Mayo Clinic

$ (NINDS funded this ANSWHR award) 

This study will provide evidence on the neuroprotective effects of estrogens with non-invasive 

imaging markers of structural and functional neuronal integrity in newly menopausal women, 

during a hormone treatment trial. This evidence would potentially have a significant impact on 

women making the decision to use hormone treatments for dementia prevention as they 

transition into menopause. Neuroprotective effects of estrogens offer the possibility of 

preventing or delaying Alzheimer's disease in menopausal women. Estrogen treatment in older 

women who were late into menopause in the Women's Health Initiative Memory Study, did not 

prevent dementia. The question remains as to whether or not estrogen can preserve neurological 

function and decrease the risk of dementia when administered early in menopause from 6-36 

months of the last menses. This project is proposed as an ancillary to the Kronos Early Estrogen 

Prevention Study (KEEPS), which is a nationwide, multi-center, randomized blinded study 

designed to provide evidence on the benefits and risks of oral and systemic estrogen treatment in 

recently menopausal women. Their goal is to test the neuroprotective effects of estrogen 

treatment in early menopause, during the 48 months of the randomized clinical trial. They will 

determine the rates of hemispheric atrophy on MRI, and the change in neuronal metabolite Nacetylaspartate (NAA) on proton MR spectroscopy (1H MRS) as a surrogate for the 

neuroprotective effects of estrogen treatment during the early postmenopausal years. In addition 

to the longitudinal serial measurements of whole brain, hippocampal and ischemic lesion 

volumes, they will use exploratory 3-dimensional voxel-based analysis of the serial MRI to 

determine the differences in the change in whole brain morphology in women who are taking 

estrogens compared to placebo. Their collaboration with the investigators of the KEEPS 

Cognitive and Affective Study will give us the ability to relate the change in neuronal metabolic 

integrity and brain morphology with the concurrent change in cognitive function in newly 

menopausal women. As an outcome of the proposed investigations, they expect to determine 
91

whether or not oral and transdermal estrogen treatment preserves brain structure and neuronal 

function during the immediate years after menopause. Several decades of follow-up are 

necessary to determine if estrogen treatment in newly menopausal women prevents Alzheimer's 

disease. This project will provide the necessary in vivo evidence on the neuroprotective effects 

of oral and transdermal estrogens in early menopause in the short term, for future large-scale, 

long term trials. The original contributions of this study to women's health research will include 

the demonstration of the effects of estrogens on longitudinal change in brain morphology and 

neuronal integrity, and the relationship between these biological changes and the concurrent 

change in cognitive function in recently menopausal women. 

1-R13-AG-039961-01A1

STRAW+10: Addressing the Unfinished Agenda of Staging Reproductive Aging

Harlow, Sioban

University of Michigan

$3,500

The purpose of this multi-disciplinary 2-day symposium is to organize and synthesize knowledge 

accumulated during the past decade in order to update the 2001 Stages of Reproductive Aging 

Workshop (STRAW) model for staging the end of reproductive life in women. We also propose 

to extend the STRAW recommendations to be more broadly applicable to the range of women's 

diverse experience of reproductive aging. We propose a multi-disciplinary symposium 

"STRAW+10: Addressing the Unfinished Agenda of Staging Reproductive Aging" to update the 

2001 Stages of Reproductive Aging Workshop (STRAW) recommendations. The menopausal 

transition is a period of critical change, including loss of fertility, increased bone resorption, 

change in lipid profiles and temporal increases in symptoms, sleep disturbances and depression. 

STRAW proposed nomenclature, a staging system, and menstrual and endocrine criteria to 

define stages of ovarian aging. It has become the gold standard for characterizing reproductive 

aging, as the Tanner Stages characterize puberty. In the past decade, understanding of the critical 

junctures in hypothalamic and ovarian function before and after the final menstrual period and 

their implications for women's health has advanced considerably. We will convene 30

investigators from key research groups in the United States and worldwide. The specific aims are 

to refine criteria for the early menopausal transition given new population-based data relating to 

follicle-stimulating hormone, antral follicle count, anti-mullerian hormone and inhibin-B; to 

assess how to include women with higher body-mass-index and who smoke in staging 

algorithms; to provide recommendations regarding staging of women following gynecological 

surgery, chemotherapy, and hormone therapy and in women with polycystic ovarian syndrome 

and chronic diseases such as HIV/AIDS; and to assess potential criteria for staging the postmenopause. The Day 1 public scientific sessions will present recent advances and discuss 

implications of new data for staging. On Day 2, small working groups will propose modifications 

to the STRAW criteria. Following discussion, final recommendations will be adopted and 

research priorities defined. The expected outcome will be a set of recommendations for 

modifying the STRAW criteria that characterize the end stages of reproductive life including 

their extension to be more broadly applicable to the range of women's experience. Short- and 

long-term research priorities will be specified including studies needed to replicate and validate 

proposed criteria as well as to address gaps in knowledge. The meeting, co-sponsored by The 
92

North American Menopause Society (NAMS), The American Society for Reproductive 

Medicine, The International Menopause Society and The Endocrine Society, will be held 

September 20-21, 2011 prior to the NAMS Annual Meeting in Washington D.C. STRAW+10 

recommendations will be presented at the NAMS meeting. A peer-reviewed executive summary 

will be published simultaneously in the co-sponsors' journals, Climacteric, Menopause, Fertility 

and Sterility; with a non-technical version published on their websites. The STRAW+10 staging 

system will facilitate consistent classification of menopausal status, ensuring comparability of 

research studies and clinical trials. Once specified, a staging system can be developed into a 

clinical tool to guide assessment of fertility and contraceptive choices, and healthcare decisionmaking. Funds will be allocated to support participation of 4 trainees/new investigators.

3-U01-AG-017719-12S1

SWAN Repository III

McConnell, Daniel S

University Of Michigan

$200,000

This competing renewal application is to provide for continued maintenance of and activities 

associated with the SWAN Repositories of serum, plasma, urine, DNA and transformed cells 

generated from a 10-year study of a population of 3302 women from 5 ethnic groups who have 

been evaluated annually prior to, during and following the menopausal transition. These 

Repositories, an arm of the Study of Women's Health Across the Nation (SWAN), are meant to 

support, facilitate and extend the Core SWAN; additionally, the Repositories provide a 

mechanism for opening the resources of SWAN to the greater scientific community. 

Implementing activities associated with three proposed specific aims of this competing renewal 

will 1) provide for the continued management of the current 1.7 million Repository specimens 

and the additional specimens that will accrue as a result of fielding SWAN IV in 2009 to 2014; 

2) expand the DNA Repository, the most frequently requested specimen type that is uniquely 

renewable because of our investment in cell immortalization; 3) promote effective information 

interchange about the SWAN Study, its data and the Repository resources through development 

of a 2-level web-based "data warehouse"; 4) provide for continued administration of the 

application review process for specimen utilization and administrative management of specimen 

distribution including Material Transfer Agreements; 5) engage in strategies to promote 

utilization of specimens; and, 6) expand the scope of the genetics studies associated with the 

SWAN study and its Repository.
93

MENTAL HEALTH

5-DP1-OD003312-05

Emotions are Emergent Events Constrained by Affective and Conceptual Processes

Barrett, Lisa

Northeastern University

$192,431

Emotional states are central to mental and physical health. NIH invests tremendous resources in 

research on emotion, much of it devoted to animal models. Ironically, this research is guided by 

a scientific paradigm that is grounded in human experience. People experience fear and see it in 

others, so scientists assume there must be a literal (modular) neural circuit for fear in the 

mammalian brain. Rats freeze when they hear a tone paired with a foot shock, so they are 

presumed to be in a state of fear (versus surprise, anger, or even a general state of alarm) and 

undergoing “fear learning.” Scientists also presume that a map of the neural circuitry of freezing 

behavior will yield a neural mechanism for fear that is largely preserved in humans, and a decade 

of neuroimaging studies have focused on locating a homologous neural circuit in the human 

brain. In the last five years, I have traced the roots of this “natural kind” model, conducted a 

comprehensive review of the literature to examine its veracity, and found it wanting (Barrett, 

2006a).1 In response, I have fashioned a new systems-level model, called the Conceptual Act 

Model, grounded in the neuroanatomy of the human brain. My model parsimoniously 

incorporates neuroscience findings from rats, primates, and humans, and explains the 

mechanisms that produce the range and variety of behavioral and introspective instances that 

they call “emotion” (Barrett, b, c; Barrett, Mesquita, Ochsner, & Gross, 2007; Barrett, Ochsner, 

& Gross, 2007; Duncan & Barrett, 2007). The Conceptual Act Model asks different – and 

perhaps better – questions about what emotions are and how they function in mental and physical 

health. The NIH Director’s Pioneer Award will allow me the intellectual freedom and resources 

to continue building evidence for the Conceptual Act Model of emotion, thereby shaping a new 

paradigm to guide the scientific study of emotion.

1-R01-MH-090071-01A1

Adjunct Aripiprazole for Symptomatic Hyperprolactinemia in Female Schizophrenia

Kelly, Deanna L

University of Maryland, Baltimore

$99,833

At least one in every two women treated with risperidone, the most frequently used dopamine 

antagonist antipsychotic, will experience hormonal side effects (i.e., menstrual abnormalities, 

galactorrhea, gynecomastia) and this same percentage will experience sexual dysfunction. These 

side effects are one of the greatest unmet needs specific to women with schizophrenia and 

currently no evidence-based treatments for this side effect are available. Our proposed study will 

test whether adjunctive aripiprazole in women will resolve prolactin related hormonal effects and 
94

will improve bone health, psychiatric symptoms, quality of life, wellness and sexual function. 

Risperidone is available generically and one of the most widely used antipsychotic medications; 

but is associated with elevated prolactin. This elevation is particularly pronounced in women and 

most recent studies show that the vast majority of women have elevated prolactin levels with 

approximately 50% also having the corresponding side effects of amenorrhea, oligomenorrhea or 

galactorrhea. Elevated prolactin may be associated with sexual dysfunction, decreased quality of 

life, medication nonadherence and decreases in bone mineral density over time. Lowering the 

dose or switching medications due to this side effect in stabilized patients is not a practical 

option in most cases. There is little evidence to guide treatment in this important area however 

dopamine agonists such as bromocriptine or amantadine may exacerbate symptoms, have lacking 

efficacy data and are associated with side effects. We have sizeable pilot data to suggest that a 

low dose of aripiprazole (10 mg/day), a dopamine partial agonist, added to Risperidone can 

improve symptomatic prolactin side effects. We will complete a double blind randomized 16-

week control trial examining adjunct aripiprazole (10 mg/day with increase to 15 mg/day at 8 

weeks if no response) vs. placebo in 70 women with symptomatic hyperprolactinemia and 

hypothesize it will be effective in the resolution of amenorrhea, oligomenorrhea and 

galactorrhea. We also hypothesize that aripiprazole will significantly improve quality of life, 

personal well-being and sexual function. And, we will examine improvements in positive, 

negative and depressive symptoms, sex hormone levels and measures of bone turnover. The 

significance and innovation of this application is high as this is a significant complaint and 

concern of women and very little evidence is available to guide treatment in women who are 

stabilized and doing well on antipsychotic treatments but develop these significant side effects. If 

funded, this important treatment research study of adjunct aripiprazole treatment will provide 

invaluable data and treatment options for thousands of women who suffer from schizophrenia 

and will help move the field towards better tailoring and personalizing antipsychotic treatment, 

particularly for women who suffer from these problems. 

MUSCULOSKELETAL SYSTEMS

1-R21-AR-059931-01A1

Health of Children Born by Mothers with Rheumatoid Arthritis

Olsen, Jorn 

University Of California Los Angeles

$193,877

Results from this study will add evidence on adverse birth outcomes and disease patterns in 

childhood and early adulthood among children born by mothers with rheumatoid arthritis (RA). 

Furthermore, using this disease as a model makes it possible to study long-term programming 

effects related to the expected impact the disease has on fetal growth. Our results will contribute 

to the sparse knowledge about the long-term impact of RA treatment during pregnancy, and 

knowledge will be generated about the potential differential impact of different RA treatments on 

the unintended outcomes. The findings can be extrapolated to the U.S. population since both 

diagnostic practice and treatments are similar. Many women with rheumatoid arthritis (RA) will 
95

have one or more pregnancies while having RA. Little is known about long term pregnancy 

outcomes for children born by women with RA but studies show more perinatal complications 

and fetal growth restriction which may activate fetal programming. Fetal programming in this 

group of children has not been investigated due to lack of large datasets that allow long-term 

follow up of children born to mothers with RA. Medications used to treat RA may also be 

harmful to the fetus, since medications are often required to manage disease activity during preconception and early stages of pregnancy. Our long-term aim is to investigate health conditions 

as measured by mortality and hospital discharge diagnoses in children born by mothers who had 

RA taking into consideration birth weight, gestational age and perinatal complications. Specific 

aims: To set up a cohort of children born by women who had been hospitalized for RA and a 

cohort of children born by mothers without this history. To record congenital malformation, 

gestational age, birth weight and other reproductive failures in these cohorts. To further 

characterize exposed pregnancies according to treatment for RA in the pregnancies that occurred 

after 1995. These cohorts can be followed for up to 30 years at present but follow may be

continued if needed. Design and Methods: A National cohort study using national registries in 

Denmark, with complete information on all Danish citizens (5.5 million and about 65,000 births 

per year) as well as long-term follow up of their children. Prescription data will be obtained from 

the National Registry of Medicinal Product Statistics and diagnoses will be obtained from the 

National Patient Registry of Hospital Discharges. Data on social and occupational factors will be 

available from the other national registers. All data in all registers are personally identifiable by 

means of the civil registration number (CPR) that has been given to all citizens from 1968 and 

forward in time. The CPR allows for linkage between registers and for linkage of biological and 

adopted children to the parents. Outcomes: Miscarriages, birth defects, adverse pregnancy 

outcomes, disease pattern in childhood and early adulthood. Exposures: RA, medical treatments 

for RA during pregnancy, RA in mother, mothers with RA who were medically treated during 

pregnancy. Statistical analyses: Data will be analyzed using Cox models. Several potential 

confounders will be taken into consideration such as age, parity, cohabitation, social conditions 

and place of living. All analyses will be performed using Stata/SAS Statistical software 

packages. Implications: The findings will add evidence on adverse birth outcomes and long term 

disease patterns in children born by mothers with RA. Knowledge will be generated about the 

potential differential impact of different RA treatments on the unintended outcomes. The results 

will indicate if more active monitoring and early intervention are needed to reduce the potentially 

increased risk for the unborn child. The study may also provide additional information on the 

potential fetotoxic effects of drugs used in treating RA. 

1-R01-AR-059357-01A1

FAK/Pyk2 Signaling Pathway And Bone Formation

Bellido, Teresita M

Indiana University

$200,000

These studies will advance our understanding of the mechanism of action of mechanical forces 

and GC on bone and have the long-term goal of developing new therapeutic strategies for 

preservation or restoration of skeletal health in patients treated with GC or exhibiting 

endogenous elevation of the steroids, such as during aging. Mechanical forces enhance bone 
96

mass and strength, whereas glucocorticoid excess (GC) decreases bone formation and increases 

bone fragility. Mechanical stimuli increase proliferation of pre-osteoblasts, accelerate osteoblast 

differentiation, and inhibit osteoblast and osteocyte apoptosis; and directly activates Wntdependent transcription and downregulates the Wnt antagonists sclerostin and Dkk1. In contrast, 

GC inhibit osteoblast differentiation and induce osteoblast and osteocyte apoptosis; and inhibit 

Wnt-dependent transcription and increase Dkk1 expression. Work leading to this application 

indicates that these converse effects might stem from opposing actions on the focal adhesion 

kinases FAK and Pyk2, which regulate interactions between cellular integrins and the 

extracellular matrix. Thus, mechanical stimuli prevent osteoblast/osteoblast apoptosis by outsidein signaling mediated by integrins resulting in activation of FAK and ERKs; and GC oppose 

these survival signals by activating Pyk2 and its target JNK, leading to inside-out signaling and 

cell detachment- induced apoptosis. Remarkably, FAK/ERK activation and anti-apoptosis 

induced by mechanical stimulation is abolished by Dkk1 or beta-catenin degradation. 

Conversely, Pyk2-dependent apoptosis by GC is inhibited by Wnts; and Pyk2 activates 

GSK3beta, the enzyme responsible for degrading beta-catenin. Based on these lines of evidence, 

it is hypothesized that there is an antagonistic interplay between mechanical forces and GC 

governed by FAK/Pyk2 signaling, which regulates the Wnt/beta-catenin pathway, bone 

formation, and osteoblast/osteocyte survival. This hypothesis will be tested by a combination of 

in vitro studies using established cell lines and primary osteoblasts and osteocytes, and in vivo 

approaches using transgenic and knockout mice. Aim 1 will determine the role of FAK-mediated 

outside-in signaling and Wnt activation in mechanotransduction. It will be investigated whether 

loading-induced anabolism is impaired in mice lacking FAK in osteoblasts and/or osteocytes, 

and whether this response is rescued by beta-catenin stabilization; and whether there is a cell 

autonomous requirement of FAK for mechano-responsiveness using osteocytes and osteoblasts 

in which FAK was knocked-down or knocked-out. Aim 2 will determine the role of Pyk2-

mediated inside-out signaling and Wnt inhibition in GC effects. It will be investigated whether 

inhibition of Pyk2 or downstream targets JNK and RhoA/Rock prevents osteoblast/osteocyte 

apoptosis, the decrease in bone formation, and the loss of strength induced by GC, by using Pyk2 

and FAK null mice and mice treated with Pyk2, JNK, or Rock inhibitors; whether beta-catenin 

stabilization or enhanced Wnt signaling prevents GC deleterious effects, using mice treated with 

GSK3beta inhibitors or Sost null mice; and whether activation of Pyk2 is responsible for Wnt 

inhibition by GC in vitro, using cells in which Pyk2 is knocked-out or knocked-down, or cells 

treated with Pyk2 inhibitors. Aim 3 will investigate whether mechanical forces and GC 

antagonize in vivo and the role of FAK in the protective action of loading when applied 

simultaneously, before, or after initiation of GC treatment. 

1-R21-AR-060811-01

A New Hip Fracture Risk Prediction Tool Based on Common Predictors and Hip 

Geometry

Chen, Zhao 

University Of Arizona

$165,622

This study will use innovative approaches, existing cohort resources, and interdisciplinary 

expertise to address a significant public health challenge: assessing the risk of hip fracture, the 
97

most detrimental type of fragility fractures. The study aims for a better risk assessment tool on 

the web that can be used by researchers and clinicians to assess an individual's hip fracture risk.

This research will test new predictors and use the assumption free modeling approach to capture 

complex and non-linear relationships of predictors with fracture risk. This research is significant 

for reducing fracture burdens in the large and growing U.S. older women population. 

Osteoporosis is a major public health problem. Women are at a particularly high risk for 

osteoporosis and 50% of women age 50 or older may suffer from a fragility fracture in their 

remaining lifetime. Hip fractures are the most detrimental type of fractures. Research has been 

conducted to assess hip fracture risk so prevention methods could be used to reduce this risk in 

the growing number of older women. However, previous risk assessment approaches are limited 

to a few variables and linear combinations of these factors. Also, there is an increasing number 

of available measures, such as bone structures and skeletal muscle mass, that can be extracted, 

for instance, from dual-energy X-ray absorptiometry (DXA), and no reliable risk prediction 

model exist based on this wealth of information. The overall goal of this study is to develop a 

comprehensive and flexible model to assess the risk of hip fracture for a specific woman. This 

will be achieved by constructing a novel predictor that classifies data that include hip structural 

geometry, sarcopenia measurements as well as risk factors identified in previous studies. The 

construction of the predictive model will be partly based on a study conducted among a large (n 

= 11,432) multi-ethnic bone cohort from the nationwide Women's Health Initiative (WHI). In 

addition, to enhance the quality of the risk prediction, computational data from finite element 

simulations will be used. There are three specific aims. The first aim is to generate a risk model, 

based on clinical data that accounts for the coupling effects of the factors involved in hip 

fracture. This research introduces a new approach in the field of hip fracture, Support Vector 

Machines (SVM), which explicitly identifies the configurations of factors that are likely to lead 

to hip fracture. The second aim is to refine the prediction/decision model from the first aim using 

both the SVM classifier and finite element modeling. A scheme has been developed to select, in 

a high dimensional space, data points that would improve the accuracy of the SVM-based risk 

prediction model. These data points would be evaluated (fracture or not) using a finite element 

model. The novelty of the proposed finite element model stems from its full parameterization so 

that the variability of the bone response can be studied with respect to variations (even small) of 

structural geometry and material parameters. The third aim is to validate and compare the SVMbased risk with and without the use of finite element analysis and develop a hip fracture risk 

calculator for the web. A cross validation will be performed using data sets from the WHI as well 

as other cohorts. The flexibility of the SVM classification approach makes it easily deployable 

on the Internet. This study will be carried out using existing cohorts by an interdisciplinary team 

with experience in epidemiology of osteoporosis research, DXA measurements including hip 

structures and sarcopenia, fracture assessments, biostatistics approaches for large datasets, high 

dimensional analysis and finite element modeling, thus making this study highly feasible. The 

study results will have an extremely significant public health impact by providing an innovative 

tool for hip fracture risk assessments. 
98

1-R21-AR-059989-01A1

Fatigue and Lifestyle Physical Activity in Lupus

Ramsey-Goldman, Rosalind

Northwestern University

$100,000

Systemic lupus erythematosus (SLE) affects up to 1.5 million persons in the US. Although 

excess mortality has decreased in SLE patients since the 1970's, substantial morbidity persists. 

Fatigue is the most disabling and enduring complaint in patients affected with this chronic 

incurable inflammatory autoimmune disease. The ramifications of fatigue are significant and 

include decreased quality of life, an increased risk of work disability and an associated increase 

in health care costs. The overall goal of this R21 application is to determine the relationship 

between two constructs, fatigue and physical activity, as a necessary first step in a broader effort 

to implement a behavior management intervention that combats fatigue by increasing lifestyle 

physical activity in persons with SLE. Thus, we propose the following specific aims and primary 

hypothesis to be tested in this R21 application: Aim 1. Evaluate the frequency, intensity, and 

duration of physical activity as measured by accelerometry to obtain patient-specific average 

daily activity counts, average daily moderate-to-vigorous minutes of activity (MVPA) (defined 

as e 2020 activity counts/min), average daily minutes of light physical activity (< 2020 activity 

counts/min), and average daily minutes of any activity (i.e., minutes of non-zero activity counts) 

in patients with SLE. Aim 2. Characterize the cross-sectional relationships between objectively 

measured physical activity and fatigue (primary outcome, Fatigue Severity Score, [FSS]) in 

patients with SLE. We will do this with and without adjustment for the major factors that 

influence fatigue including sleep and wake disturbance, depression, anxiety, and pain 

interference using PROMIS tools, and SLE disease activity and severity. The adverse clinical, 

social, and economic implications of fatigue support the critical need for an improved 

understanding of factors contributing to fatigue in SLE, a research priority identified in the 

NIH/NIAMS monograph entitled, The Future Directions of Lupus Research. Systemic lupus 

erythematosus (SLE) affects up to 1.5 million persons in the US. Although excess mortality has 

decreased in SLE patients since the 1970's, substantial morbidity persists. Fatigue is the most 

disabling and enduring complaint in patients affected with this chronic incurable inflammatory 

autoimmune disease. The ramifications of fatigue are significant and include decreased quality of 

life, an increased risk of work disability, and an associated increase in health care costs. The 

overarching goal of this R21 application is to explore ways to improve the measurement of two 

constructs, physical activity and fatigue, as a necessary first step in a broader effort to use a 

behavior management intervention to lower fatigue scores by increasing lifestyle physical 

activity in persons with SLE. We propose a novel application of a relatively new technology to 

objectively measure physical activity (triaxial accelerometry, which provides a validated 

measurement of daily physical activity in the community dwelling setting). In addition, we 

propose to measure covariates of fatigue using computerized adaptive tests (CATs) patientreported outcomes (PROs) that have been developed using state-of-the-art cognitive, qualitative, 

quantitative and health survey methodologies as part of the NIH-funded Patient-Reported 
99

Outcomes Measurement Information System (PROMIS). PROMIS tools were developed to 

standardize measurement of self-reported health domains affected by many chronic illnesses and 

these tools offer the advantages of minimizing patient burden and maximizing precision. Using a 

cross-sectional study design, the following specific aims will be tested in this R21 application: 

Aim 1. Evaluate the frequency, intensity, and duration of physical activity as measured by 

accelerometry to obtain patient-specific average daily activity counts, average daily moderate-tovigorous minutes of activity (MVPA) (defined as e 2020 activity counts/min), average daily 

minutes of light physical activity (< 2020 activity counts/min), and average daily minutes of any 

activity (i.e., minutes of non-zero activity counts) in patients with SLE. Aim 2. Characterize the 

cross-sectional relationships between objectively measured physical activity and fatigue (primary 

outcome, Fatigue Severity Score, (FSS) in patients with SLE. We will do this with and without 

adjustment for the major factors that influence fatigue including sleep and wake disturbance, 

depression, anxiety, and pain interference using PROMIS tools, and SLE disease activity and 

severity. The adverse clinical, social, and economic implications of fatigue support the critical 

need for an improved understanding of factors contributing to fatigue in SLE, a research priority 

identified in the NIH/NIAMS monograph entitled, "The Future Directions of Lupus Research". 

5-R01-AR-044422-13

NARAC: The Genetics of Rheumatoid Arthritis

Gregersen, Peter K

Feinstein Institute For Medical Research

$175,363

This renewal application has the overall goal of identifying all of the major common genetic 

variants that underlie susceptibility to rheumatoid arthritis, and to begin to identify rare 

susceptibility alleles, if they exist. In preliminary data we have identified a number of candidate 

genes and regions on the basis of linkage analysis in multiplex RA families, as well as by whole 

genome association studies using approximately 550,000 SNPs on a panel of over 900 RA 

patients and matched controls. We now wish to identify the specific causal variants and 

understand their mode of action. In specific aim 1 we will identify the causal genetic variants 

within the common genes that confer risk for rheumatoid arthritis. We have already identified 

several genes and regions of interest, including STAT4 on chromosome 2q. In specific aim 1a 

we will replicate these initial associations in case-control datasets totaling up to 5,000 patients. 

Various methods of genomic control for population stratification will be utilized for these 

replication studies. In specific aim 1b we will carry out fine mapping of candidate regions. This 

will generally involve haplotypic analysis using custom sets of SNP markers. In specific aim 1c 

we will utilize various approaches to identify the likely causative genetic variants in the gene 

under study. Examples of the approaches to be used in specific aim 1c are given for STAT4. In 

specific aim 2, we will apply a staged approach to identify gene-gene and gene-environment 

interactions that contribute to RA susceptibility. The top performing markers in the univariate 

analyses of specific aim 1a and 1b will be examined for interactions using Classification and 

Regression Tree (CRT) as well as traditional logistic regression methods. Top performing 

models will be tested in replication datasets of cases and controls. In specific aim 3, we will 

identify rare genetic variants that contributes to RA susceptibility. This specific aim is based on 

preliminary analysis indicating that "slightly deleterious" SNPs (sdSNPs) are a significant 
100

component of the genetic burden underlying complex disease. These sdSNPs are enriched in the 

low frequency (MAF <5%) component of the SNP population. We will initially investigate a 

limited number of candidate genes with high-throughput sequencing on the Solexa platform, 

along with follow up analysis in large case control datasets. Larger scale and more 

comprehensive approaches to this issue may be employed in the later years, depending on 

technical advances in the field.

5-R01-AR-049772-09

Predictors of Pregnancy Outcome In SLE and APS

Salmon, Jane E

Hospital for Special Surgery, New York, NY

$192,240

Pregnancy complications in women with the antiphospholipid syndrome (APS) and/or SLE 

include recurrent miscarriage, preeclampsia, placental insufficiency, and intrauterine growth 

restriction (IUGR). The mechanisms leading to placental and fetal injury in vivo are 

incompletely understood and treatment remains sub-optimal. We have identified complement as 

an early effector in pregnancy loss and/or IUGR associated with placental inflammation in a 

mouse model of APS and shown that complement activation causes the release of antiangiogenic factors and abnormal placental development. The PROMISSE Study (Predictors of 

pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus 

Erythematosus) is a first-time effort to translate our novel findings in mice to humans and 

determine if elevations of complement split products predict pregnancy complications in patients 

with antiphospholipid (aPL) antibodies and/or SLE. In the first 4 years of this prospective, 

observational study of pregnant patients grouped and analyzed according to the presence or 

absence of aPL antibodies and preexisting SLE, we have enrolled 342 pregnant patients in 7 

centers, obtained detailed medical and obstetrical information monthly, and serially collected 

plasma, serum, DNA, RNA, and urine. Preliminary data suggest that elevated levels of 

complement activation products antecede and predict poor fetal outcome, consistent with our 

hypothesis that complement is a proximal mediator of fetal loss and IUGR. We propose to 

increase our target sample size from 400 to 700 pregnant patients to maintain study power given 

lower than expected outcome rates, and to leverage the infrastructure and rich collection of 

patient data and samples by expanding the array of biomarkers and scope of adverse pregnancy 

outcomes. Specifically, in Aim 1 we will determine whether elevations of split products 

generated by activation of complement pathways predict poor fetal and/or maternal outcome in 

patients with aPL antibodies and/or SLE and, in Aim 2, whether the balance of circulating 

angiogenic and antiangiogenic factors predicts preeclampsia or delivery of IUGR infants. In Aim 

3, a new direction, we will use the PROMISSE cohort to affirm in humans our recent findings in 

mice, that certain anti-DNA antibodies cross-react with N-methyl D- aspartate receptors 

(NMDAR) and cause neuronal death with ensuing cognitive and behavioral impairment. We 

propose to quantitate anti-NMDAR antibody levels throughout pregnancy in PROMISSE SLE 

patients and test the hypothesis that in utero exposure to maternal anti-NMDAR antibodies alters 

behavior and cognitive development in offspring by evaluating cortical function tasks in 12 

month and 3.5 year old children. This competitive renewal and extension of the PROMISSE 

Study provides an outstanding opportunity to translate knowledge from mouse models to 
101

patients, define pathogenic mechanisms, identify predictors of poor pregnancy outcome in APL 

and/or SLE, and define novel therapeutic targets to prevent such outcomes. Patients with 

systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies are at increased 

risk for miscarriage, preeclampsia and fetal growth restriction - major causes of maternal, fetal, 

and neonatal morbidity and mortality in the US and worldwide - whose etiology and mechanism 

remain unknown and for which therapy is limited. In addition to causing placental dysfunction, 

maternal autoantibodies may also directly impair fetal brain development. Identification of 

biomarkers that predict poor pregnancy outcome in these patients will elucidate mechanisms of 

disease, define targets for treating patients, and generate clinically applicable indicators to permit 

initiation of interventional trials in patients at greatest risk for pregnancy complications.

1-R21-AI-095921-01

Sexual Dimorphism and Dysregulated Immune Responses in SLE: The Role of Leptin

La Cava, Antonio

University Of California Los Angeles

$ (NIAID funded this ANSWHR award)

In this application we will explore new mechanisms that may contribute to the increased 

susceptibility to develop systemic lupus erythematosus ( SLE) in females. We will investigate 

the role of a hormone that is expressed in much higher concentration in females as a possible 

major contributor to the pathogenesis of SLE. The role of this hormone, leptin, will be 

investigated in great detail for its capacity to inhibit the activity of cells that suppress 

autoimmunity in SLE, as preliminary work seems to suggest. This proposal aims to advance the 

current understanding of the cellular and molecular immune events that associate with the 

increased susceptibility to develop systemic lupus erythematosus (SLE) in females. Gender 

disparities associate with several biological differences that most apparently involve an evident 

dissimilarity between sexes in the levels of sex hormones and their receptors. However, although 

very important, the differences in the expression and responsiveness to sex hormones may not be 

sufficient to fully explain the increased incidence of SLE in females. During the past decade, our 

group has been interested in investigating the effects of the hormone adipokine leptin on immune 

responses. We and others have shown that this sexually dimorphic hormone - found at 

concentrations 5-10 times higher in females than in males with similar body mass index - has 

proinflammatory activities that greatly favor the development and the progression of several 

autoimmune diseases including SLE. We have also shown that leptin constraints the ability of 

regulatory T cells to suppress autoreactive immune responses in vitro and in vivo, and together 

with others we have shown that regulatory T cells can modulate SLE disease activity. Here we 

propose to dissect the effects of leptin on regulatory T cells in SLE by testing the hypothesis that 

elevated levels of leptin in females can modulate key characteristics of the regulatory T cells in 

SLE. Three integrated aims will study the influence of leptin on the phenotype and function of 

regulatory T cells in SLE at the cellular, molecular and biochemical levels. By identifying 

specific events that can be modulated by leptin in SLE, we aim to ultimately identify surrogate 

markers of therapeutic intervention that could lead to a better management of the disease. 
102

5-R21-AR-056404-02

A Link Between Parity, Trunk Muscle Function, And Degenerative Spondylolisthesis

Cholewicki, Jacek

Michigan State University

$ (NIAMS funded this ANSWHR award for FY11)

The costs associated with the treatment of degenerative low back disease make it one of the top 5 

most expensive conditions in the American healthcare economy. Women suffer from DS at a 3-9 

times higher rate than men, as yet, without a clear explanation. If the number of childbirths and 

cesarean sections predisposes women to this condition later in life, proactive planning of 

effective intervention strategies and educational campaigns would be prudent. This study will 

examine relationships between pregnancy, cesarean section (CS) and other abdominal surgery, 

trunk and abdominal muscle deficiency, and degenerative spondylolisthesis (DS) in older 

females. The key question is whether pregnancy and/or CS mediated trunk muscle deficiency 

could be a precipitating factor in the development of DS later in life. Three specific aims are to 

determine whether: (1) parity/CS/other abdominal surgeries are associated with DS, (2) trunk 

muscle deficiency is associated with DS, and (3) parity/CS/other abdominal surgeries are

associated with trunk muscle deficiency. The costs associated with the treatment of degenerative 

low back disease make it one of the top 5 most expensive conditions in the American healthcare 

economy. DS is considered one of the major causes of low back pain among the older 

population. Women suffer from DS at a 3-9 times higher rate than men, as yet, without a clear 

explanation. Previous studies documented relationships between pregnancy and low back pain, 

and suggested abdominal muscle deficiency as an underlying cause. Of special concern is the 

effect of CS. The rates of CS rose three-fold over the last 3 decades and may cause significant 

public health problems regarding DS in coming years. We propose to conduct a case-control 

study of 200 DS patients and 200 age-matched (in 5 year age groups) controls, including a more 

detailed assessment of trunk muscle function in 80 DS and 80 matched control subjects. Group 

designation will be based on a DS diagnosis from a sagittal view x-ray. The 400 subjects will be

administered a detailed questionnaire regarding their parity, CS, previous surgeries, and other 

potential covariates. A subset of 80 subjects from each group will in addition undergo a physical 

examination of their abdominal and trunk muscle function and quantitative assessment of motor 

control. Physical exam will include abdominal muscle and hip extension tests. These tests 

examine the ability of the abdominal and paraspinal muscles to stabilize pelvis and the lumbar 

spine during simple hip flexion and extension maneuvers. Motor control tests will quantify 

muscle reflex latencies in response to sudden trunk perturbations, and postural control while 

balancing on an unstable seat. Both delayed muscle reflex responses and poor postural control 

are associated with low back pain and constitute predisposing risk factors to future low back 

problems. Poor motor control could lead to spine instability, chronic problems and degenerative 

changes in the spine over time. All measures will be quantified (continuous or categorized) and 

used in the regression and chi-square analyses to test the hypotheses. Innovative aspects of this 

proposal comprise of quantifying muscle function objectively and documenting variables related 

to parity in women with and without DS, which gives a better chance of finding any relationships 

that might exist. 
103

5-R21-HL-093068-02

Sexual Dimorphism of Skeletal Muscle

Huxley, Virginia H

University of Missouri-Columbia

$ (NHLBI funded this ANSWHR award) 

This project is to develop and validate a skeletal muscle model for the study of the primary 

functions of the smallest blood vessels in age-matched male and female animals of the same 

species, the mouse. The 2 primary functions of the microcirculation 1) blood flow to 

metabolizing tissue, and 2) the movement of nutrients from blood to tissue as well as the removal 

of wastes from tissue to blood, appear to differ between males and females in health and 

cardiovascular disease including hypertension and secondary to type 2 diabetes. As materials 

distribute themselves between blood and tissue, so too will fluids move between compartments; 

thus if exchange regulation differs between males and females it is likely that volume 

distribution will also differ. Therefore it is imperative to have access to a model to learn the 

differences and similarities between the sexes as the data from males, disease incidence and 

severity and subsequent treatment strategies will not apply equally to females. Skeletal muscle 

(SKM) microvasculature has been studied extensively with respect to respiratory gas and nutrient 

exchange, volume distribution, and blood flow control, into and within the organ, in health and 

disease. This R21 is in response to a PFA requesting development of models for the study of 

function in males and females. This is terribly important as most studies of SKM have been 

conducted in males (animals and humans) with the presumption that the data apply equally to 

both sexes. Evidence from multiple studies accumulated over the last decade is making it clear 

that this assumption in error. One model used widely for in vivo study is the rodent cremaster, a 

thin muscle derived from the abdominal wall that raises and lowers the testes. Surprisingly, no 

microvascular skeletal muscle preparation of equivalent metabolic and fiber type substitutes 

presently for the cremaster that facilitates study of both males and females. This proposal aims to 

rectify this lack by validating the abdominal wall skeletal muscle preparation in males and 

female rodents. The hypothesis is that microvascular skeletal muscle functions do not differ 

between age-matched males and females of the same species. Accordingly, 3 aims will be carried 

out in in situ and isolated abdominal muscle microvessels from age- and strain-matched female 

and male mice: Aim 1 will assess whether sexual dimorphism exists with respect to blood flow 

regulation from measures from microvascular diameter to selected endothelium-dependent and -

independent agents. Given recent data they expect to reject their hypothesis as they anticipate 

that a) arterioles from males will develop greater basal tone and b) the dose-response relationship 

for the endothelium-dependent dilation will differ between males and females. Aim 2 will assess 

whether sexual dimorphism exists with respect to exchange regulation from measures from 

measures of microvessel solute permeability (Ps). Given their data, they expect to reject their 

hypothesis as they anticipate that a) venules from males will be leakier than those from females, 

b) basal arteriole and capillary barrier properties will not differ by sex, and c) the vasoactive 

agents will produce a variety of exchange responses reflecting differences in sex-specific 

mechanisms regulating solute distribution between the vascular and tissue compartments of 

males and females. Aim 3 will compare the sex, age, organ and species matched diameter (Aim 

1) and exchange data (Aim 2) from microvessels as they lay in the living tissue and following 

isolation from the tissue. This is an incredibly opportunity to make these comparisons as not all 
104

tissues are amenable to study in situ and it is assumed that the data from the isolated vessels 

reflect the behavior in the tissue. Data from this project will form the foundation for future 

genetic, biochemical, and physiologic studies of microvascular function in males and females. It 

is imperative that they validate a model for study of microvascular function in both sexes to 

understand intelligently the sex-dependent mechanisms regulating vascular function in health 

and dysfunction in disease. With the knowledge the foundation, and provide rational means for 

prevent and treating vascular disease specific to the needs of males and females. 

1-R03-AR-057518-01A1

Delayed Pubertal Development on The Mechanism Of Bone Loss At Maturity

Yingling, Vanessa R

Temple University

$ (NIAMS funded this ANSWHR award)

Fracture risk in the elderly has its origins during growth and development. A delay in the onset 

of puberty results in both low bone mass and an increased incidence of stress fracture in young 

women. Therefore, the failure to accrue peak bone mass during the adolescent years represents a 

missed opportunity to optimize bone mass during one's life. 1. Osteoporosis is "a pediatric 

disease with geriatric consequences". Simply stated, suboptimal skeletal. 2. Development in 

childhood and adolescence may result in decreased bone strength and an increase in lifetime 3 

fracture incidence. A delay in the onset of puberty (primary amenorrhea) correlates with both 

low bone mass; 4. and an increased incidence of stress fracture. Suboptimal bone accrual may 

have long term consequences. 5. Even with current treatment options as studies that treated 

amenorrheic dancers for 2 years with hormone 6 replacement therapy found no difference in 

bone mineral density between treated and placebo groups. The 7 most significant factors during 

development may be nutritional and lifestyle factors. Therefore, our overall goal 8 is to ascertain 

the affect of delayed pubertal development on the mechanism of bone loss at maturity. 9 Density 

measures alone, although widely used clinically, cannot identify osteoporotic subjects who will 

sustain 10 fractures, due to the large overlap in bone mass measures in individuals with fractures 

and those without 11 fractures. Other factors including bone size, architecture and material 

properties must be considered. We 12 have recently developed a texture analysis approach using 

Gabor filters, which is capable of providing insight 13 into bone structure from localized texture 

information on a pixel level. The texture approach is therefore a 14 potentially powerful tool in 

analyzing trabecular bone texture where orientation, shape and architecture as well 15 as density 

are the fundamental components. Our previous work was analyzing 2D images but we propose to 

16 transfers this approach to 3D images. This novel approach will indicate not only bone mass 

changes but 17 changes in orientation which may be very significant later in life. In Aim #1, We 

will test the hypothesis that 18 the mechanism and magnitude of bone loss in a mature animal is 

dependent on bone development. 19 Specifically, delayed pubertal onset will alter the 

architecture of bone that will affect the mechanism of 20 bone loss at maturity. Pubertal delay 

will be completed by gonadotropin releasing hormone antagonist 21 (GnRH-antagonist) 

injections. At 50 days of age changes in bone morphology will be evaluated using a novel 22 3D 

texture analysis. The following biomarkers will be measured to assess the response of pubertal 

delay on 23 systemic changes in bone metabolism osteocalcin (a marker of bone formation) and 

N-telopeptide of collagen 24 type I (NTx) (a marker of bone resorption). Serum estradiol and 
105

IGF-1 will also be assayed to confirm the 25 hormonal response to the protocol. Flourescent 

histomorphometry will assess bone formation rates on 26 trabecular bone. At maturity (150 days 

of age) the experimental rats will undergo ovariectomy surgery to 27 model post menopausal 

bone loss. Changes in bone morphology will be evaluated using static and dynamic 28 

histomorphometry, micro-CT and texture analysis. By using a systems approach relating 

environmentally 29 induced delayed puberty to bone growth, we propose to gain a new 

understanding of the important relationship 30 between growth and its variability and the bone 

structure we become heir to during the aging process 31. 

The Osteoarthritis Initiative (OAI)

Knee osteoarthritis (OA) is the most common cause of disability in adults. The "Osteoarthritis 

Initiative (OAI): A Knee Health Study" is a nationwide research study that will help researchers 

gather more information about the physical changes that occur prior to the onset of arthritis 

symptoms or before OA gets worse. The purpose of this study is to examine people who have 

knee OA or are at high risk for knee OA; information will be used to better understand how to 

prevent and treat knee OA Knee OA causes more health problems and medical expenses that any 

other form of arthritis. Symptoms of OA can range from stiffness and mild pain to severe joint 

pain and even disability. Previous research has shown that certain factors, such as knee pain, 

prior knee injury or knee surgery, OA of the hand, or obesity, may lead to knee OA. The OAI is 

a multicenter, observational study of knee OA that will collect information on potential 

biomarkers for OA and trends in OA onset and progression. The OAI will recruit and follow 

participants who have knee OA or are at high risk for developing knee OA for at least a four-year 

period at one of four clinical centers. Blood and urine collection, magnetic resonance imaging 

(MRI), and X-rays will be completed at each of four annual follow-up visits. A questionnaire and 

physical examination at screening will assess for risk factors for the development and 

progression of knee OA. Levels of knee pain and physical disability will be assessed at study 

start and at each of the follow-up visits by questionnaire and examination.

N01-AR022258 

The Osteoarthritis Initiatives II -- Data Coordinating Center

Nevitt, Michael

University of California San Francisco 

$600,000

This Data Coordinating Center oversees data collection, imaging, functional assessments, 

collection and archive of biospecimens from the four Osteoarthritis Initiative Clinical Centers 

and provides the data and images to the research community through the OAI web site: 

http://oai.epi-ucsf.org/datarelease/ . Two of the 4 clinical sites are also co-funded by ORWH. 

N01-AR22259

The Osteoarthritis Initiatives II -- Clinical Center

Hochberg, Marc

University of Maryland Baltimore, Baltimore, MD

$25,000 
106

N01-AR22261

The Osteoarthritis Initiatives II -- Clinical Center

Jackson, Rebecca

Ohio State University, Columbus, OH

$25,000 

NEUROLOGY/NEUROSCIENCES

1-R21-NS-075608-01

Modifiable Risk Factors In Stroke Incidence And Mortality Among Women

Wang, Sophia

Beckman Research Institute Of The City Of Hope, Duarte, CA 

$ (NINDS funded this ANSWHR award) 

Successful completion of these aims will permit evaluation of the population impact of a decade 

of profound transition in obesity, physical activity, and MHT use on women's stroke incidence 

and mortality, and provide insight into the interplay between these and other relevant exposures. 

This proposal focuses on the etiology of stroke incidence and causes of stroke mortality and 

emphasizes common, modifiable, behavioral risk factors in ways that can facilitate future 

population-wide stroke prevention efforts. The California Teachers Study spans more than a 

decade of profound transitions in women's health behaviors, including increasing physical 

inactivity and obesity, and decreasing use of hormone therapy. By examining how exposures to 

these common, modifiable risk factors over a woman's lifespan influences rates and risk of stroke 

incidence and mortality, this study will provide critical new knowledge that can serve as the 

basis for behavioral public health interventions that benefit women on a population-wide scale. 

Stroke is the third leading cause of death in the United States (U.S.) and women account for 60% 

of all deaths from stroke. Major shifts in modifiable exposures over the past decade - increasing 

obesity and physical inactivity and decreasing menopausal hormone therapy (MHT) use - are 

changing the profile of women's health, but their effect on stroke among women is unclear. The 

California Teachers Study (CTS), a prospective cohort study that has actively followed 133,479 

female California public school professionals for a broad range of health outcomes since 1995, is 

poised to evaluate how these societal transitions in modifiable exposures affect incidence of and 

mortality from stroke. The unique repository of life course exposure data on modifiable risk 

factors in the CTS cohort provides a near-singular resource for prospective assessment of 

women's health risks associated with long-term history of physical activity, longitudinal 

anthropometry data on body fat distribution, and detailed MHT use. Our specific aims address 

the impact of these shifting exposures both individually and together on stroke incidence and 

mortality, both overall and among the two major stroke subtypes (ischemic and hemorrhagic). In 

Aim 1, we will determine the impact of obesity and physical inactivity on the rates, risk, and 

population attributable fraction of incident and fatal stroke. Our detailed questionnaires permit us 

to evaluate the effect of lifelong and changing patterns of obesity phenotypes (defined as a 

combination of temporal changes in overall adiposity with adult body fat distribution) and 

physical activity, including by age and recency. In Aim 2, we will determine whether the effects 
107

on rates, risk and population attributable fraction observed from obesity and physical inactivity 

(Aim 1) become more pronounced in the years following widespread cessation of MHT use 

(after 2002). To accomplish these aims, we will calculate age-adjusted and age-specific annual 

incidence and mortality rates, standardized to the U.S. population in 2000. To calculate risk 

associations, we will use time-dependent exposure data on these key exposures from teenage 

years to old age and analyze associations with stroke risk and mortality using statistical 

approaches that account for missing data and secular changes in exposures. We will calculate the 

population attributable fraction for each etiologic risk factor, and by time period when MHT was 

widely used versus the recent sharp decline in use. 

5-R21-NS-071210-02

Sex differences in the CNS during disease

Voskuhl, Rhonda R

University of California Los Angeles

$ (NINDS funded this ANSWHR award)

This is an exploratory (R21) grant to determine the effect of sex chromosomes and sex hormones 

on the central nervous system's response to an immune attack using the multiple sclerosis model, 

experimental autoimmune encephalomyelitis. This proposal will establish a model system to 

determine the effect of sex chromosomes and sex hormones on a variety of neurological diseases 

characterized by a sex difference. Numerous neurological diseases are characterized by a sex 

difference. The neuropathology often includes infiltration of immune cells, with this immune 

infiltration potentially contributing to disease pathogenesis. Since it is known that sex differences 

exist in the immune system, this confounds investigations into sex differences in the CNS. Thus, 

they will use bone marrow chimeras to investigate sex differences in the CNS. By varying sex 

chromosomes or sex hormones in hosts reconstituted with a common immune system, one can 

ascertain the role of sex chromosomes and sex hormones on the brain response to injury. They 

will use one of the most inflammatory of all CNS disease models, the multiple sclerosis model, 

experimental autoimmune encephalomyelitis (EAE), to show applicability of this approach to a 

variety of neurological diseases. They will employ mice which differ in the complement of sex 

chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex 

chromosomes in the absence of confounding effects of exposure to different types of sex 

hormones. Specifically, in aim #1 they will determine whether the greater severity of EAE in 

XX, as compared to XY-, mice is due to sex chromosome effects in the CNS. In aim #2, they 

will determine if the sex chromosome effect in the CNS during EAE is due to the dose of X or Y 

genes. Finally in aim #3, they will use mice which differ in gonadal type, female vs. male, while 

having the same sex chromosome complement (XX vs. XX Sry) to determine whether the 

greater severity of EAE in female, as compared to male, mice is due to sex hormone effects in 

the CNS. 
108

1-R01-AG-042189-01

Epigenetics of the Aging Astrocyte: Implications for Stroke

Sohrabji, Farida

Texas A&M University Health Science Center 

$100,000

The risk and disability associated with stroke increases with age. In order to develop more 

effective therapies for this disease, this application will focus on age-related changes in a specific 

brain cell called the astrocyte. Our studies using an animal model show that middle-aged females 

sustain more brain damage after stroke than younger females and this is associated with 

functional changes in the neuroprotective ability of astrocytes. We will seek to understand global 

age-related changes in this cell type so as to develop markers for disease severity as well as new 

therapeutic targets. Stroke is the leading cause of disability in the US and with heart disease, the 

leading cause of death. The risk for stroke with consequent functional disability is increased with 

age, and in women this risk is elevated after the menopause. Paradoxically, hormone therapy at 

menopause increases the risk for stroke. Animal models of stroke confirm that stroke severity is 

worse in aged animals as compared to younger animals. In middle age, our recent data shows 

that female rats sustain a greater degree of tissue damage in the cortex and striatum as compared 

to younger females. Middle aged males, on the other hand, do not differ significantly from 

younger males in the extent of cortical infarction. This age difference in cortical cell loss is also 

paralleled by functional changes in astrocytes, a specific brain support cell. Astrocytes play a key 

role in normal and pathological conditions. Following stroke, astrocytes are rapidly mobilized to 

the peri-infarct area, detoxify the injured brain via glutamate uptake and fluid efflux and secrete 

growth factors known to promote angiogenesis and neuronal survival and neurogenesis. 

Astrocytes culled from the ischemic cortex of middle aged female rats show profound loss of 

protective functions including a reduced ability to sequester glutamate, decreased growth factor 

release, increased release of chemokines and increased ability to recruit leukocytes. These 

changes are consistent with increased infarct volume observed in older females. Hence in this 

proposal we will determine age and sex-specific epigenomic changes in astrocytes obtained from 

the ischemic cortex, to determine critical translational and transcriptional modulators. In Specific 

Aim 1 we will determine age-related changes in the expression of small non-coding RNA. 

MicroRNA, a key translation regulatory element, regulates large gene networks, and have been 

shown to play a central role in cell senescence and injury (stroke). In Specific Aim 2 we will 

determine age-related changes in DNA and histone methlyation patterns. Methylation patterns of 

specific leucines associated with activation (H3K4me3 and H3K9ac) or repression (H3K9me3 

and H3K27me3) of gene transcription will be targeted. These complementary approaches will 

allow us to develop a molecular fingerprint of the aging astrocyte. Finally, in Specific Aim 3, 

select molecular targets will be manipulated using (1) miRNA mimetics or antagomirs and (2) 

demethylases to reverse age-specific patterns in astrocytes. Data gathered from these studies is 

expected to aid in the eventual identification of epigenomic changes that predict disease severity 

and facilitate discovery of therapeutic targets. 
109

OBESITY/OVERWEIGHT

1-R21-DK-092718-01

Ovarian Hormone Suppression And Regulation Of Adipogenesis In Women

Kohrt, Wendy M

University of Colorado Denver

$229,500

Women are largely protected against abdominal adiposity prior to the menopause. The loss of 

estrogen at the time of the menopause triggers an increase in abdominal fat accumulation, which 

likely contributes to increased risk for the metabolic syndrome, type 2 diabetes mellitus, 

coronary artery disease, and hypertension. The proposed studies will test the novel hypothesis 

that estrogen deficiency results in abdominal fat gain by triggering an increase in the number of 

fat cells. Estradiol (E2) deficiency triggers weight gain, and specifically abdominal fat gain, in 

women. The shift toward central adiposity after menopause likely contributes to increased risk 

for the metabolic syndrome and associated chronic diseases (i.e., type 2 diabetes, coronary artery 

disease, hypertension). The long-term aim is to understand the mechanisms by which E2 

deficiency mediates increases in abdominal adiposity. The primary aim (PA1) of the R21 is to 

determine whether ovarian hormone suppression in premenopausal women, which is known to 

cause fat gain, triggers an increase in adipogenesis (i.e., increase in cell number) in abdominal 

adipose tissue. This will be assessed by measuring the changes in cell size distribution and the 

incorporation of deuterium (2H) into DNA of cells in the non-stromal (i.e., mature adipocyte) 

fraction. Secondary aims are to determine: SA2) effects of ovarian hormone suppression on 

mRNA expression of factors involved in adipogenesis (C/EBP1, PPAR3) and markers of 

macrophage infiltration (CD68, Emr-1) and inflammation (IL-6, TNF-1); and SA3) whether new 

adipocytes arise from non-resident bone marrow progenitor (BMP) cells using cell surface 

markers (Notch 4, Platelet-derived Growth Factor Receptor (PDGFR) 2, Integrin 15, CD36) that 

enable detection by flow cytometry. To achieve these aims, 24 premenopausal women will be 

studied before and after 30 and 60 days of ovarian hormone suppression via gonadotropin 

releasing hormone agonist therapy with add-back of placebo (GnRHAG+PL) or estradiol 

(GnRHAG+E2). Hypotheses are: H1a) GnRHAG+PL for 60 days will result in a larger increase 

in small adipocytes (<40 5m) when compared with GnRHAG+E2. Because fat mass increases 

during GnRHAG+PL, an increase in the number of small adipocytes will be interpreted as an 

increase in adipogenesis and not as evidence of adipocyte atrophy; H1b) The incorporation of 2H 

in the non-stromal cell fraction DNA will be increased in response to GnRHAG+PL, as 

compared with GnRHAG+E2. Because the non-stromal fraction contains mature adipocytes, an 

increase in 2H- enriched DNA should reflect adipogenesis; H2) Ovarian hormone suppression 

will increase mRNA expression of factors associated with adipogenesis, macrophage infiltration, 

and inflammation (C/EBP1, PPAR3, CD68, Emr-1, IL-6, TNF-1) when compared with baseline 

(before vs after GnRHAG+PL) and when compared with E2 add-back (GnRHAG+PL vs 

GnRHAG+E2); and H3) Ovarian hormone suppression will increase BMP-derived adipocytes 

when compared with baseline (before vs after GnRHAG+PL) and when compared with E2 add-
110

back (GnRHAG+PL vs GnRHAG+E2). To the best of our knowledge, this will be the first in 

vivo study of the role of E2 as a regulator of adipogenesis in humans. Because it is believed that 

adipocytes are programmed to achieve a certain volume of fat, an increase in adipocyte number 

would lead to a gain in fat mass that would be very difficult to reverse. Thus, identifying 

strategies that effectively prevent an increase in adipogenesis during ovarian hormone 

withdrawal would be of high clinical importance. 

1-R01-DK-092608-01

Intestinal Satiation In Roux-en-Y Gastric Bypass Rats: Brain Mechanisms And Sex 

Differences

Asarian, Loredana

University of Zurich

$200,000

Bariatric surgery, in particular Roux-en-Y gastric bypass (RYGB) surgery, is currently the only 

effective therapy for morbid obesity, which is a grave and growing national health problem. The 

mechanisms through which RYGB increases satiation and reduces eating and body adiposity are 

poorly understood. It is thought that increased intestinal satiation caused by the entry of ingesta 

more distally into the small intestine, leading to increased release of the gut hormones GLP-1 

and PYY, is the major cause of early satiation at meals and reduced overall intake. This proposal 

builds on classical rat models to test RYGB's effects on intestinal satiation, at the levels both of 

gut-brain signaling and of brain neural processing. In addition, as > 80% of RYGB patients are 

women, the application includes experiments to assess whether sex differences in the physiology 

of intestinal satiation affect RYGB outcome. This work should lead to new insights that may 

help improve how bariatric surgery is done and may suggest targets for pharmaceutical 

alternatives to bariatric surgery in patients for whom is it not desired or appropriate. Bariatric 

surgery, in particular Roux-en-Y gastric bypass (RYGB) surgery, is currently the only effective 

therapy for morbid obesity, which is a grave and growing national health problem. The 

mechanisms through which RYGB increases satiation and reduces eating and body adiposity are 

poorly understood. It is thought that the major cause of early satiation at meals and reduced 

overall intake is increased intestinal satiation caused by the entry of ingesta more distally into the 

small intestine, i.e., into the jejunum, thus leading to increased release of the gut hormones 

glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY). This proposal adapts 

classical rat models to test RYGB's effects on intestinal satiation, at the levels of both of gutbrain signaling and of brain neural processing. RYGB will be done by one of the co-PIs who 

performs the technique both experimentally and clinically, assuring a close match between the

experimental model and the clinical standard. The experiments include tests of nutrient-specific 

controls of ingestion that are hypothesized to be affected by RYGB. In addition, both the release 

patterns and the satiating potency of endogenous GLP-1 and PYY are tested. The brain work 

builds on progress in the past decade concerning the neural processing of intestinal negativefeedback controls of eating in the caudal brainstem and in the hypothalamus. Finally, because 

about twice as many women than men suffer from morbid obesity in the USA and because about 

85% of patients electing RYGB are women, all the proposed experiments include tests of 

physiological sex differences, both male-female difference and estrogen-regulated effects in 

females, the latter especially relevant to understanding and treating the increase in adiposity 
111

associated with menopause. Three Specific Aims are proposed: (1) Determine whether the 

satiating actions of intra-jejunal infusions of Ensure, Intralipid and glucose are increased by 

RYGB surgery, including the impacts of adipose-tissue loss and of sex differences, i.e., male vs. 

female and estradiol-treated vs. untreated ovariectomized rats; (2) Determine the effects of 

RYGB surgery on brain c-Fos expression in response to intra-jejunal infusions of Ensure, 

glucose and Intralipid, and determine the neurochemical phenotypes of neurons expressing cFos, including the impact of sex differences, i.e., male vs. female and estradiol-treated vs. 

untreated ovariectomized rats and (3) Determine the effects of RYGB on neural signaling 

mechanisms underlying the satiating actions of intra-jejunal infusions of Ensure, Intralipid and 

glucose in male vs. female and in estradiol-treated vs. untreated ovariectomized rats. State-ofthe-art behavioral, physiological and molecular techniques are used. Thus, the work (1) should 

help inform behavioral and nutritional counseling for RYGB patients, (2) may suggest strategies 

for improvement in the RYGB technique, and (3) should provide rational bases for the 

development pharmaceutical tools to augment or replace RYGB, which is especially desirable 

for patients who do not desire bariatric surgery or for whom it is not recommended. 

1-U01-DK-094416-01

Weight Management in Obese Pregnant Underserved African American Women

Klein, Samuel

Washington University

$100,000

This project will test a novel lifestyle intervention to help obese socioeconomically 

disadvantaged African American women achieve healthy weight control during and after 

pregnancy and improve the health of their offspring. The treatment will be given through an 

existing national home visiting program, Parents As Teachers, which will facilitate sustainability 

and nationwide dissemination, if effective. Maternal obesity and inappropriate gestational 

weight gain (GWG) increase both maternal and neonatal morbidity and mortality. In addition, 

offspring of obese women are at increased risk for neurodevelopment delay, becoming obese, 

and developing metabolic diseases. Women who are socio-economically disadvantaged (SED), 

especially from African American (AA) populations, are particularly susceptible to adverse 

pregnancy-related outcomes because of their high prevalence rates of obesity. Therefore, 

successful weight management during pregnancy in SED, AA women has considerable public 

health implications. We have experience in testing lifestyle interventions among SED nonpregnant women that have been implemented and sustained within community organizations 

such as Parents As Teachers (PAT), a national home visiting program that provides parent-child 

education and services free-of-charge to high needs women, prenatally and post-partum, through 

up to 25 home visits per year until kindergarten. We propose to conduct a 24-month (6-month 

prenatal and 18-month post-partum) randomized, controlled trial in obese SED AA women to 

evaluate the ability of an innovative lifestyle intervention program (PAT-i-), delivered by PAT 

parent educators during prenatal and post-partum home visits, to improve maternal and 

neonatal/infant weight, metabolic and health outcomes. An extensive programmatic evaluation 

will determine the applicability of the PAT+ intervention in real world settings by measuring 

programmatic reach, implementation, acceptability, and sustainability. If effective, PAT+ can be 
112

disseminated through this national organization, which currently reaches over 249,000 mothers 

and 319,000 children participating in 2,173 PAT programs across all 50 states. 

1-U01-DK-094463-01

Lifestyle Interventions in Overweight and Obese Pregnant Women

Pi-Sunyer, Xavier

St. Luke's-Roosevelt Institute For Health Sciences, New York, NY

$100,000

The prevalence of overweight and obesity in reproductive age US women is extremely high. 

These women when pregnant tend to gain higher than the recommended GWG, produce 

disproportionally fat babies, and retain much of the GWG post-partum. It is unknown whether 

maintaining GWG within the new lOM guidelines will produce leaner babies who have less risk 

of becoming obese adults, and will lead to less retention of GWG in women. A trial 

demonstrating these outcomes could lead to public health recommendations. A randomized 

controlled trial is proposed to study the effect, in a cohort of racially and ethnically diverse group 

of overweight and obese pregnant women, of an Intensive Lifestyle Intervention (ILI) compared 

to Usual Care (UC) on gestational weight gain (GWG), infant fatness, and mothers' post-delivery 

weight retention. Women in the ILI arm will receive intensive counseling during pregnancy and 

group counseling after delivery regarding behavior, nutrition, and physical activity change. Visits 

to counselors will be weekly and additional telephone and internet contacts will occur. The 

mothers' will be assessed at 14 and 36 weeks of pregnancy and at 12 weeks and 52 weeks postdelivery. The measurements will be anthropometry, whole body MRI, EchoMRI, and whole 

body plethysmography (BodPod). The infants' measurements will be anthropometry, whole body 

MRI, EchoMRI, and whole body plethysmography (PeaPod) for fatness 12 weeks and 52 weeks. 

Mothers and children will have cardio-metabolic risk factors measured in plasma. Data will be 

collected regarding mothers' dietary intake and physical activity (questionnaires and 

accelerometry) to assist in counseling. Other data to be collected include questionnaires on 

quality of life, socio-economic status. Careful record will be kept of expenses in providing the 

ILI, so that cost analysis of the intervention can be calculated. The study is powered on the 

primary outcome, fatness of the infants at birth. We require 180 participants to attain appropriate 

power. We will enroll 210 so as to allow for some dropouts along the way. Each mother will be 

followed during pregnancy and for a year post delivery. Each infant will be followed for a year 

after birth. We have the ability o continue to follow these participants if further funding is 

forthcoming, as they are all local to or hospital's catchment area and our own physicians. If aims 

are achieved, namely that both children and mothers profit from the intervention, there should be 

a paradigm shift in how overweight pregnant women are treated. At present, there is a dearth of 

behavioral advice and intervention relating to GWG and physical activity provided to these 

women. Positive results from our study would provide evidence for ILI preventative 

intervention. 
113

PAIN

1-R13-DE-022238-01

Co-morbid Chronic Pain Conditions - Mechanisms, Diagnosis and Treatments

Cowley, Allen W

The TMJ Association

$28,740

Up to 50 million Americans experience one or more of the following six conditions, also seen in 

many TMD patients - they are chronic fatigue syndrome, endometriosis, fibromyalgia, interstitial 

cystitis, temporomandibular disorders, and vulvodynia. The estimated cost of the six pain 

conditions alone is $80 billion, which, because of the lack of understanding their cause and the 

availability of effective treatments, is essentially wasted. This meeting will accelerate the 

scientific research which will contribute to the reduction of the suffering and financial burden 

these conditions place upon the patients, their loved ones and our nation as a whole. The Sixth 

Scientific Meeting of The TMJ Association, "Comorbid Chronic Pain Conditions - Mechanisms, 

Diagnosis and Treatments", is scheduled to be held on June 5-7, 2010 at the Federation of 

American Societies for Experimental Biology Conference Center in Bethesda, Maryland. The 

need for this meeting and that of previous meetings has been based on two important factors. 

First, the number of people affected in the U.S. by temporomandibular disorders (TMD) is 

estimated to be approximately 36 million. The majority are women in their childbearing years. 

The physical, psychological and financial burden on these patients is compelling. Second, there 

continues to be a dearth of scientific understanding of the etiology of these conditions upon 

which to base diagnostics and develop safe and effective treatments. To stimulate research in this 

field, The TMJ Association has organized five scientific meetings beginning in the year 2000. 

These meetings have convened scientists in the temporomandibular disorders field and other 

disciplines to characterize and address the multiple symptoms and frequently found comorbid 

conditions in TMD patients. The theme of the sixth scientific meeting builds upon evidence from 

the five previous meetings demonstrating that TMD are a complex family of conditions 

influenced by genetics, gender, environmental and behavioral triggers mediating the 

vulnerability of patients to TMD and typically manifesting as more than jaw and muscle pain and 

jaw dysfunction. The sixth meeting will focus on the pathophysiological processes underlying 

the chronic pain conditions which co-exist with TMD and constitute comorbid chronic pain 

conditions (CCPC). They include: chronic fatigue syndrome, chronic headache, endometriosis, 

fibromyalgia, irritable bowel syndrome, interstitial cystitis, and vulvodynia. The meeting will 

engage key leaders and representatives from funding and patient advocacy organizations who 

will develop recommendations to advance research in this field. The specific aims of the meeting 

are to determine: 1. What is currently known about underlying mechanisms of CCPC; 2. What 

we need to know about CCPC (e.g., case definition, diagnostics); 3. What research areas are 

most promising to pursue (best approaches, resources); 4. How best to foster the development of 

treatment modalities for CCPC; 5. What approaches are necessary to encourage, train, and 
114

sustain a CCPC research community; and 6. What high-risk research areas have the potential to 

substantially advance our understanding of CCPC. 

OD-11-317

Centers of Excellence in Pain Education

NIDA, for the NIH Pain Consortium

$50,000

The NIH Pain Consortium is establishing “Centers of Excellence for Pain Education” at Medical, 

Dental and Nursing schools across the nation, in an effort to give health care professionals a 

better understanding of pain as part of their basic education, with the aim of improving pain 

treatment while reducing the risk of prescription opioid abuse. These Centers will establish 

curriculum on pain which will be used in courses at these Centers, and the adoption of these 

curricula at other academic institutions will be encouraged by various forms of outreach. All 

materials will be accessible on the NIH Pain Consortium’s website.

5-R03-AR-057489-02

Epidemiology of Patellofemoral Pain Syndrome: Identifying Gender Specific Risk Factors

Boling, Michelle C

University of North Florida 

$ (NIAMS funded this ANSWHR award in FY11)

Patellofemoral pain syndrome (PFP) is one of the most common chronic knee conditions 

affecting young adults, with an increased occurrence in females. Individuals suffering from this 

condition may experience symptoms lasting multiple decades, limiting their participation in 

physical activity, and predisposing them to chronic diseases associated with inactivity such as 

obesity, arthritis, coronary artery disease, diabetes, and cancer. The results from this 

investigation may be used to identify those at greatest risk to PFP and develop appropriate 

prevention programs to decrease the occurrence of this condition, particularly in females. 

Patellofemoral pain syndrome (PFP) is one of the most common causes of knee pain, affecting 

approximately 25% of the physically active population, with females being 2-3 times more likely 

to develop PFP compared to their male counterparts. The overall objective of this proposal is to 

determine the mechanical (structural and biomechanical) and non-mechanical (demographic and 

psychosocial) risk factors that are associated with PFP and identify the risk factors specific to 

females and males. The approach will be to use a prospective cohort design to identify risk 

factors that are associated with incident PFP. The central hypothesis is that individuals who 

develop PFP will have altered movement patterns, abnormal lower extremity anatomical 

alignments, decreased lower extremity strength, previous history of knee injury, previous 

participation in a low number of athletic activities, decreased levels of hardiness, and increased 

number of healthcare visits. A secondary hypothesis is that females and males will have different 

risk factor profiles. They will utilize baseline risk factor data that has been collected on 5690 

freshman (males=3482, females= 2208) during the summers of 2005- 2008 at the following 

military academies: United States Naval Academy, United States Military Academy, United 

States Air Force Academy. Baseline risk factor data was collected through a current NIH funded 

project (R01-AR054061001), entitled JUMP-ACL. Each participant will contribute follow up 
115

time for incident PFP until they graduate from their respective academy. Medical record reviews 

will be performed to identify those participants who developed PFP during their respective 

follow-up time. Based on the two years for the proposed investigation, follow up time will be 4 

years for all participants enrolled in the JUMP-ACL investigation from 2005-2008. Poisson 

regression analyses will be performed to determine the risk factors for PFP. Additionally, males 

and females will be analyzed separately to determine gender specific risk factor profiles. The 

proposed project is making an efficient use of already collected risk factor data by adding 

analysis of a new outcome (PFP) that would not otherwise be investigated by the JUMP-ACL 

project. Additionally, the proposed investigation is cost effective due to no funds being required 

for baseline data collection. Their rationale for the proposed investigation is that there is a crucial 

need for prospective studies that identify the risk factors for PFP so that more focused prevention 

strategies can be developed that are appropriately gender specific. 

1-R01-HD-065740-01A1

A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response

Brown, Candace S

University Of Tennessee

$200,000

The proposed research is relevant to public health because we will determine the efficacy of 

gabapentin in women with provoked vestibulodynia, a highly prevalent and distressful condition 

that causes severe pain in the outer vagina, and which consumes large amounts of health care 

resources and has few treatment options. We will also identify predictors of treatment response 

that will have clinical applicability to other chronic pain syndromes, and is relevant to NIH's 

mission to investigate coexisting pain conditions in order to identify common etiological 

pathways for developing therapeutic targets. Approximately 14 million U.S. women have 

provoked vestibulodynia (PVD), a type of localized vulvar pain which causes major disruption in 

the everyday lives of up to 60% of affected women and negatively impacts sexual function in 

45%. The financial burden imposed on the health care system is also significant, as these women 

visit multiple clinicians and specialists, and try numerous, unproven treatments. To date, few 

randomized controlled trials (RCTs) have been conducted to establish evidence based protocols 

for PVD management. The first immediate goal is to conduct a multicenter RCT of gabapentin 

treatment for PVD. Gabapentin was selected because of its efficacy in treating other neuropathic 

pain conditions and the promising, preliminary data on its use in PVD. This is a significant 

research project because PVD is a highly prevalent, chronic pain condition that is costly to the 

health care system and that currently has limited management options available to affected 

women. The second immediate goal is to define psychophysiologic measures of gabapentin 

response and to define mechanistically-based PVD subtypes, which may be related to 

abnormalities in central sensitization, muscle hypertonicity, and autonomic dysregulation. 

Identifying predictors of treatment response in PVD would have clinical applicability to other 

chronic pain syndromes, and is consistent with NIH's mission to investigate coexisting pain 

conditions in order to identify common etiological pathways and develop therapeutic targets. The 

specific aims are (1): to test the prediction that pain from tampon insertion (primary outcome 

measure) is lower in PVD patients when treated with gabapentin compared to when treated with 

placebo. Additional outcome measures include reported intercourse pain and 24-hour pain, and 
116

(2) to test the prediction that gabapentin treatment will reduce mechanical allodynia, reduce area 

and duration of hypersensitivity induced by intradermal capsaicin, reduce vaginal muscle pain to 

palpation, decrease the number and intensity of somatic tender points, and increase cardiac beatto-beat variability. This 16-week, randomized, double-blind, placebo-controlled, crossover study 

will enroll 120 women between 18-50 years of age who report tenderness localized to the vulvar 

vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. 

Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects 

when treated with gabapentin (up to 3600 mg/d) compared to when treated with placebo. The 

approach is innovative because it focuses on an understudied condition, in a multicenter setting, 

using a novel outcome measure (the tampon test), and a newly developed web-based recruitment 

and patient-reporting tool. Data management will include a mechanism-based analysis of drug 

effectiveness. These study outcomes will ultimately lead to our long-range goal of identifying 

underlying pathophysiologic mechanisms of PVD in order to create evidence-based differential 

diagnoses of subtypes of PVD for more effective and cost-effective management options. 

PHYSICAL ACTIVITY

National Health and Nutrition Examination Survey (NHANES) 

Survey of Physical Activity Measures

$170,000, in partnership with the National Cancer Institute

The NHANES measures of physical activity, sleep, and muscle strength will provide important 

data relevant to women across the life span from a nationally representative sample. The 

proposed measures will be collected from youth, adults, and older adults, as NHANES has no 

upper age limit. 

Objective measurement of physical activity and sleep. (ages 6+)

Accelerometer data from NHANES 2003-2006 highlighted the dramatic decline in physical 

activity as children move into adolescence. This decline was particularly striking for girls, whose 

prevalence of adherence to the recommended 60 min/d of moderate or greater intensity physical 

activity dropped from 35% for ages 6-11y to 3% for ages, 12-15 y. This contrasts with adherence 

prevalence for boys of 49% for ages 6-11 y and 12% for ages 12-15 y. The adolescent boys’ 

prevalence dropped to a quarter of that for the younger ages, while the girls’ prevalence dropped 

to less than 10%. For both sexes, the amount of physical activity was fairly constant through 

adulthood and then declined further at ages 50-60 years. On the other end of the age spectrum 

from the adolescent decline in activity, poor sleep quality is an issue for women as they age. The 

accelerometer protocol will allow objective assessment of sleep duration and efficiency in a 

nationally representative sample, with oversampling of those ages 60 y and older.

Measurement of upper body strength by hand-grip dynamometer. (ages 12+) 

Objective measures of muscle strength have not been collected across a wide age range in a 

national sample for several decades. This measure will provide a measure that is well associated 

with total body strength for adolescents through older adults. The recent focus on childhood 

obesity should be balanced with concerns about health-related fitness. Muscle strength is an 

important aspect of fitness for youth that is related to ability and propensity to engage in physical 
117

activity. Muscle strength has also been shown to be an important predictor of independent living 

as well as mortality among older adults. The NHANES strength data will allow evaluation of sex 

differences in prevalence of low muscle strength across the full age spectrum.

PREVENTION

1-R13-NR-013623-01

Advancing Transdisciplinary Translation for Prevention of High-Risk Behaviors

Fishbein, Diana Hanna

Research Triangle Institute, Research Triangle Park, NC 

$50,000

Both the social and basic sciences have recently made notable advances in identifying factors 

that influence development of high-risk behaviors, with potentially significant implications for 

their prevention. Translation of this information from the basic to the prevention sciences and 

back again is, however, lacking. We propose to hold two round-table meetings for 60 experts to 

"connect the dots" across the translational spectrum by identifying pressing scientific questions 

in prevention research, as well as the collaborations and capabilities needed to address them with 

a goal to apply this knowledge toward developing more effective preventive interventions and 

policies, thus having extraordinary potential significance for mental and public health policy. 

Several cross-cutting, forward-thinking investigators on the leading edge of both the social 

(geospatial mapping, contextual behavioral science, developmental psychology, education, social 

media) and basic sciences (genetic epidemiology, epigenetics, neuroscience, chemistry) have 

recently made notable advances in identifying factors that influence emergence of high-risk 

behaviors. This information has potentially significant implications for the prevention of highrisk behaviors, given that etiological social and neurobiological risk factors may also operate as 

moderators and/or mediators of intervention outcomes. Transfer and application of this 

knowledge from the basic to the prevention sciences and back again is, however, lacking. This 

transfer is particularly needed to understand differences in individual response to interventions to 

prevent high-risk behaviors and develop new interventions tailored for an individual's risk

factors. We propose to use the R13 mechanism to hold two round-table meetings that convene a 

core of 60 relevant experts and advisors to "connect the dots" across the translational spectrum 

by identifying pressing scientific questions in risk behavior prevention research, as well as the 

collaborations and capabilities needed to address them. These meetings are designed to facilitate 

the relevance, operational feasibility, and utility of a transdisciplinary translational program of 

research to gain a better understanding of the mechanisms underlying individual differences in 

intervention responsivity. Meetings will promote a cross-disciplinary integration of theoretical 

perspectives and empirical methods to: a) identify high priority scientific questions yet to be 

addressed in the prevention sciences that may be informed by a new generation of research 

suggesting that neurogenetic mechanisms correlate and interact with environmental conditions to 

promote or interfere with behavioral change in response to interventions; b) conceive of novel 

psychosocial and technological preventive intervention approaches and policy developments that 

incorporate transdisciplinary scientific findings, c) discuss an educational agenda for early career 
118

researchers to move into translational prevention; d) identify potentialities for new collaborations 

that will facilitate the advancement of a Translational Network for prevention research, e) 

conduct a survey of participants for their perceptions before and after the conferences regarding 

team science, needs for translational competencies, and market analysis; f) address ethical issues 

arising from inclusion of genetic and neurobiological markers of risk for behavioral problems, g) 

publish an open-access monograph of the proceedings; h) publish two special journal editions 

authored by a subset of attendees who will reanalyze their clinical trials datasets using state-ofthe-art statistical techniques to elucidate mechanistic effects of their interventions, and report 

progress and preliminary findings from new collaborations forged during the meetings.

REPRODUCTIVE HEALTH/DEVELOPMENTAL BIOLOGY

Y2-OD-1200-01

Adrenal hyperplasia among adolescent patients polycystic ovarian syndrome (Bench to 

Bedside) 

Stratakis, C.

NICHD; SUNY Downstate

$135,000

Polycystic ovarian syndrome (PCOS) is a heterogeneous group of disorders presenting with 

hyperandrogenism in adolescents and young women. The etiology of this condition remains 

unknown, despite its many identified links to insulin resistance, hypertension and metabolic 

syndrome, as well as its potential connection to adrenogenital disorders, such as the various 

forms of congenital adrenal hyperplasia (CAH). We propose that there is a subgroup of patients 

with PCOS who actually have non-CAH primary forms of bilateral adrenocortical hyperplasia 

(BAH). To investigate this possibility, we propose to study the hypothalamic-pituitary-adrenal 

axis (HPAA) over the next 2 years in 100 young girls and women (ages 16 to 25 years) that we 

will compare to 30 age- and race-matched normal females. Patients will be recruited primarily 

(although not exclusively) from a busy New York City clinic run by the Pediatric Endocrine 

Division at the Infants and Children's Hospital of Brooklyn at Maimonides and SUNY 

Downstate. All patients will undergo standard testing of the HPAA including oral low- and highdose dexamethasone (DEX)-suppression testing (Liddle’s test). “Paradoxical” rise of cortisol 

and/or other steroid metabolites in response to DEX is considered a sensitive test for the 

diagnosis of BAH. Patients with such responses will be molecularly investigated for the known 

causes of BAH (GNAS, PRKAR1A, PDE11A, and PDE8B mutations). The transcriptome will 

be studied in patients who had paradoxical responses to DEX but are mutation-negative (to these 

genes). The goal of this study is to identify any possible contributions of the BAH phenotypes 

and genotypes to the pathophysiology of PCOS, a yet unknown factor in the etiology of this 

multifaceted disorder. This proposal addresses the possibility that PCOS may be linked to a 

form of primary adrenal hyperplasia. The clinical protocol resulting from this project will 

provide new knowledge about the diagnosis, natural history, and potential treatment of PCOS. 

Our laboratory has committed resources to the investigation of adrenal disorders and cAMP 

signaling. From the available evidence, we certainly expect that this pathway is involved in 
119

steroidogenesis. Our findings will lead to improved guidelines for treatment, and ultimately, 

new, therapies for PCOS. This work represents a new initiative; it is not covered by existing 

protocols; it represents an intramural/extramural collaboration and was stimulated by the 

availability of this special funding mechanism, as existing laboratory and clinical budgets of the 

participating investigators could not possibly cover this endeavor.

5-R01-HD-064398-02

Genetic Determinants of Uterine Fibroids in African-American and Caucasian Women

Aissani, Brahim

University Of Alabama

$83,333

Currently, the only effective and non-invasive therapy to treat uterine fibroids is a hormone 

(gonadotropin releasing hormone) - based therapy with serious side effects. The knowledge to be 

gained from this study could, at some point in the near future, lead to the development of the first 

genetic counseling protocol for fibroids and ultimately to a more appropriate therapy. Uterine 

leiomyomas (ULs) are the most common pelvic tumors in women of reproductive age, 

accounting for over 600,000 hysterectomies annually in the United States. Several lines of 

evidence support a genetic liability in the pathogenesis of ULs, yet no susceptibility gene is 

known. Advances in research on the genetics of ULs (fibroids) have so far been limited by the 

paucity of genetic epidemiologic studies and infrastructure to conduct them. The goal of this 

epidemiologic study is to evaluate the contribution of a region of Chr.1q43 that predisposes to 

uterine fibroids but remains inadequately investigated. Genetic predisposition to ULs has been 

studied primarily in the context of two rare inherited autosomal-dominant conditions, the 

hereditary leiomyomatosis and renal cell cancer (HLRCC) and the multiple cutaneous and 

uterine leiomyomatosis (MCUL1) syndromes, where germline mutations were found in the gene 

on Chr. 1q43 encoding the tricaboxylic acid cycle (Krebs cycle) fumarate hydratase (FH) 

enzyme. However, a direct role of this important metabolic housekeeping gene in tumorigenesis 

remains to be proven. Inactivating FH mutations have rarely (< 1-2% of the tumors analyzed) 

been observed in nonsyndromic (common) ULs; however, loss of FH appears to be a significant 

event in the pathogenesis of a subset of these tumors. Furthermore, several observations support 

the existence of an alternative or additional candidate gene on Chr.1q43 acting alone or 

interacting with FH to increase the risk of ULs in susceptible individuals: 1) the absence of FH 

genotype-phenotype correlations, 2) the marked genetic heterogeneity in ULs, and 3) the failure 

to observe ULs or multiple leiomyomatosis in siblings or parents of cases with fumarase 

deficiency, a severe recessive disorder. Taken together, these observations underscore the 

importance of exploring an extended FH region in a population-based study of ULs. To this end, 

they will generate a high-density single nucleotide polymorphism genotyping data across a 2-Mb 

region spanning FH in subsets of African American (n=582) and Caucasian (n=455) women 

enrolled in the NIEHS-Uterine Fibroids Study. This is a well designed cross-sectional study of 

ULs that includes data on most potential confounders. Their study is not intended to shift any 

paradigm about the origins of ULs; rather it will extensively investigate the role of FH in 

nonsyndromic ULs, dissect the intricate genetic correlates of Chr.1q43 markers in the expression 

of the disease phenotype and evaluate their effects in two populations with a marked difference 

in disease risk. Recent updates in the genome databases have revealed new potential candidate 
120

genes for tumor growth and important structural variations including a large (~ 308 Kb) copy 

number variation in the vicinity of FH; these new findings further justify a study with the 

proposed depth and extent of genetic coverage. This study will likely open new avenues for 

research and may ultimately redirect current preventive and therapeutic approaches or enhance 

their efficacy. 

5-R01-HD-064402-02

Xenograft Study on Growth-Control of Human Uterine Leiomyomata

Kurita, Takeshi

Northwestern University

$83,333

A better understanding of how uterine leiomyomata grow is essential to developing novel 

therapies for this tumor. While the dependency of uterine leiomyoma on ovarian steroids is well 

established, the relative importance and function of 172-estradiol versus progesterone are yet to 

be clarified. Recently, they developed a method of growing human uterine leiomyoma tumors in 

immunodeficient mice. The xenografts of human uterine leiomyoma faithfully preserved the 

phenotype and hormone responsiveness of original human tumors in situ, and their growth was 

totally dependent on progesterone and 172-estradiol. Using this novel xenograft model in 

combination with viral gene transduction, they will elucidate the cellular and molecular 

mechanisms of human uterine leiomyoma growth. The ultimate goal of this study is to elucidate 

the molecular mechanisms of uterine leiomyoma (UL) formation and growth, and identify 

potential targets for novel therapeutic and preventive treatments of this disease. UL is a benign 

tumor of the myometrium that affects millions of reproductive-age women. Surgical removal of 

the entire uterus (hysterectomy) is the primary treatment option, and management of UL puts an 

enormous burden on the healthcare system. Therefore, finding a new therapeutic treatment 

replacing surgery is of great interest to the public. Due to the absence of a proper research model 

system reflecting characteristics of the original tumors, the biological nature and the causes of 

UL are poorly understood. Although growth dependency of UL on ovarian steroids (172-

estradiol and progesterone) is well established, the relative importance and function of 172-

estradiol and progesterone are yet to be clarified. In spite of accumulating evidence for the 

essential role of progesterone in UL growth, no research model has clearly demonstrated a 

growth-promoting effect of progesterone on UL. To elucidate the function of ovarian steroids in 

UL, they have established a novel xenograft model in which tissue fragments of human 

leiomyoma were grafted beneath the renal capsule of immunodeficient mice. The size of the 

leiomyoma xenografts increased in response to 172- estradiol and progesterone as demonstrated 

by cell proliferation and accumulation of extra-cellular matrix. In contrast, xenograft growth 

induced by 172-estradiol and progesterone was blocked by the anti-progestin RU486, indicating 

the essential role of progesterone and progesterone receptor (PR) in leiomyoma tumor growth. 

Previously, 172-estradiol has been thought to be the primary stimulus for UL growth. 

Surprisingly, 172-estradiol by itself neither increased nor maintained tumor size. Likewise, 

progesterone alone did not affect UL growth in this model. Although not mitogenic, 172-

estradiol was required for expression of PR, and was essential for progesterone to act on UL 

xenografts. Their study clearly demonstrates the pivotal role of progesterone in growth and 

maintenance of UL. The results of their xenograft model agree with clinical observations, yet 
121

radically change the paradigm of steroid hormone-regulated human UL growth by emphasizing 

the importance of progesterone instead of 172- estradiol. Using the novel xenograft model, they 

will elucidate the cellular and molecular mechanisms of human UL tumor growth controlled by 

172-estradiol and progesterone. 

5-R01-HD-060530-02

Genetic Studies of Uterine Leiomyomata

Morton, Cynthia Casson

Brigham And Women's Hospital

$83,334

The importance of this research is to further their understanding of the biology of uterine 

leiomyomata. Uterine leiomyomata, or fibroids, are the most common pelvic tumors in females 

and occur in a minimum of 20-25% of women of reproductive age. Uterine leiomyomata may 

serve as an important model system to study the genetic events that distinguish benign and 

malignant neoplasms. A more complete understanding of the genes involved in the pathogenesis 

and pathobiology of uterine leiomyomata will provide a foundation for future diagnosis, 

management and treatment of uterine fibroids. Uterine leiomyomata, or fibroids, are the most 

common pelvic tumors in females and occur in a minimum of 20- 25% of women of 

reproductive age. Although benign neoplasms, they constitute a major public health problem as 

25-50% of affected women experience debilitating symptoms including excessive menstrual 

bleeding and pelvic discomfort as well as reproductive failure. Fibroids are the major indication 

for hysterectomy accounting for over 200,000 procedures annually in the United States. It is 

highly likely that there is a genetic liability to develop fibroids; they are at least three times more 

frequent in African American than Caucasian women (representing a serious health disparity) 

and twin-pair correlations for hysterectomy in monozygotic twins are about twice that observed 

in dizygous twins. Despite these findings and enhanced research in this area in recent years, 

much remains to be known about this racial predisposition and specific genes involved in the 

pathogenesis of fibroids. Also of particular interest and of unknown molecular mechanism, 

fibroids rarely proceed to their malignant counterpart, uterine leiomyosarcoma. Thus, it follows 

that uterine leiomyomata may serve as an important model system to study the genetic events 

that distinguish benign and malignant neoplasms. Consistent chromosome aberrations have been 

observed in fibroids indicating the location of genes involved in these tumors. A number of 

cytogenetic subgroups have been identified and they have been successful in using positional 

candidate gene approaches in determining that two high mobility protein genes, HMGA2 and 

HMGA1, located on chromosomes 12 and 6, respectively, participate in the pathobiology of 

uterine leiomyomata, in addition to MYST4, located on chromosome 10. The major goal of this 

proposed application is to further their understanding of the biology of uterine leiomyomata. 

Experiments are focused on continuing to develop and use a uterine leiomyomata tissue bank and 

database for gene discovery, gene expression studies, and genotype-phenotype correlations. A 

variety of molecular and cytogenetic approaches will be used in the identification, isolation and 

characterization of genes involved in the pathogenesis and pathobiology of uterine leiomyomata. 

Chromosomal rearrangements in tumor cells will provide biological landmarks for positional 

cloning experiments. Transcriptional profiling offers a powerful approach to discriminate genes 

that differentiate fibroids of different cytogenetic subgroups as well as fibroids of variant 
122

histologies from their normal smooth muscle counterpart, the myometrium, or their malignant 

counterpart, uterine leiomyosarcoma. Lastly, the potential role of sequence variants in HMGA2 

will be explored by a variety of mechanistic experiments to assess their role in uterine 

leiomyomata. 

5-R01-HD-061821-03

Identification of Genes Predisposing to Pelvic Floor Disorders

Cannon Albright, Lisa A.

University of Utah

$66,667

This research has a major potential to affect public health in the prevention of PFDs: they may be 

able to identify high risk populations who can be identified at a young age, studied and possibly 

targeted for prevention; and at a later stage in the development of PFDs, special interventions can 

be studied and possibly implemented in women at risk for recurrence of their condition. 

Someday, identification of these high risk populations may be as general as familial risk, or as 

specific as specific gene screening. The investigators propose a unique and powerful 

collaboration between basic and clinical scientists in Utah to identify genes affecting 

predisposition to pelvic organ prolapse (POP). The co-PIs both have significant experience, Dr. 

Norton in Pelvic Floor Disorder (PFD) genetics and Dr. Cannon-Albright in predisposition gene 

identification. The investigators will access the Utah Population Database, a computerized 

genealogy of Utah combined with decades of medical data from the two largest healthcare 

systems in Utah (serving 90% of the state), to identify and recruit surgically treated cases of POP 

(1,250 cases in 5 years). All POP cases sampled will be genotyped with the Illumina 610Q SNP 

marker set. The PIs will apply multiple different genetic analyses to this resource of genotyped 

POP cases to aid in the identification of predisposition genes. The record linkage of medical 

procedure codes (identifying surgeries performed on each patient) to individual genealogy data 

allows us to identify all genetic relationships among the POP cases. They will perform genomewide association analysis, using software they have developed which allows inclusion of both 

independent and related cases. They will identify all genetic relationships between the sampled 

POP cases and perform linkage analysis in informative, high-risk POP pedigrees. They will 

identify chromosomal regions shared Identical by Descent (IBD) in very distantly related cases 

in these pedigrees, and they will identify IBD sharing within the small subset of POP cases (2%) 

who are inbred. Initial collaborative analysis of data obtained by Dr. Norton's NIH funded study 

of affected PFD sib-ships has already provided significant evidence for a predisposition gene 

localization on chromosome arm 9q, and suggestive evidence for at least one other locus on 

chromosome 1. In summary, they will create a population-based resource of surgically treated 

POP cases, they will pursue established and new methods to identify and localize predisposition 

genes affecting POP, and they will begin a detailed search for the chromosome 9 gene they have 

localized. 
123

5-R01-HD-061811-03

Comprehensive Evaluation of Prolapse Meshes by an Interdisciplinary Research Team

Moalli, Pamela A.

Magee-Womens Research Institute

$66,666

Prolapse (i.e., abnormal descent) of the pelvic organs is a common costly condition that 

negatively impacts the lives of millions of women world-wide. Biologic and synthetic meshes 

are often used in the surgical repair of prolapse due to improved anatomical outcomes over 

native tissue repairs; but with little scientific data on which to base the selection of a particular 

product. Unfortunately, the complications associated with certain meshes cause unacceptably 

high rates of morbidity including infection, tissue contraction, vaginal discharge, and pain. In 

this proposal, they aim to establish a comprehensive mesh testing center in which previously or 

newly marketed prolapse meshes can be objectively tested and the next generation of prolapse 

meshes can be developed based on specific scientific criteria. Each year roughly 200,000 U.S. 

women undergo a surgery to repair pelvic organ prolapse. Biologic and synthetic meshes are 

widely used in prolapse repairs to improve anatomical outcomes over native tissue repairs which 

currently have a failure rate of over 30%. To date, however, there is little scientific data to guide 

surgeons in the selection of a particular product. As a result, meshes are used based on the 

recommendations of a local vendor and consequently, are placed in women on a trial and error 

basis. There is growing evidence, however, that the complications associated with prolapse 

meshes cause unacceptably high rates of morbidity including infection, mesh shrinkage, mesh 

erosion, mesh exposure, pelvic, rectal and bladder pain and dyspareunia. Such complications 

have become significant enough for the FDA to recently release a warning about mesh use, 

especially when it is placed transvaginally. In this proposal, they therefore, aim to establish an 

interdisciplinary team of scientists dedicated to the comprehensive testing of previously or newly 

marketed prolapse meshes and for the development of the next generation of graft materials 

based on specific scientific criteria. In the first phase of the study, they determine how 

biochemical and structural changes in the prolapsed vagina impact passive and active mechanical 

behavior so as to develop a mesh in which these deficiencies are repaired or compensated for, 

allowing us to restore the prolapsed vagina to the nonprolapsed condition. In the second phase, 

they hypothesize that the shortcoming of current prolapse meshes is that they are too stiff. While 

this results in a repair with increased tensile strength, it occurs at the expense of tissue function 

with accelerated tissue contraction, decreased elasticity and compliance, and deterioration of 

smooth muscle function. To test their hypothesis, they implant commonly used synthetic 

prolapse meshes into the vagina of nonhuman primates with prolapse using the gold standard 

surgical procedure (the abdominal sacrocolpopexy) and then define the cellular, biochemical and 

biomechanical impact on the vagina at 6 months post implantation. Eventually, they will implant 

meshes transvaginally to characterize the distinct host response to this surgical approach. In the 

third phase, they explore the development of future grafts for prolapse surgery. They hypothesize 

that because of its bioinductive effects, a combined biologic/synthetic mesh will be superior to a 

synthetic mesh alone in restoring vaginal structure and function. They propose that a key yet 

poorly developed component of prolapse repairs is the re-establishment of smooth muscle 

reactivity and therefore, test the use of a temporary biologically active scaffold in achieving this 
124

process. In this way, this grant proposal provides a mechanism to establish the first team of 

scientists dedicated to the comprehensive unbiased evaluation of prolapse meshes as a means of 

educating both current and future prolapse surgeons, and the public regarding potential problems 

associated with certain materials. Indeed, the development of such a group is imperative for 

protecting the health of women. 

5-R01-HD-061787-03

Wireless Remote Abdominal Pressure System: Developing A More Comprehensive 

Understanding Of Physical Activity And Its Association With Incidence, Progression And 

Recurrence Of Pelvic Floor Disorders

Nygaard, Ingrid E.

University of Utah

$66,667

The effect of strenuous physical activity on new or recurrent pelvic floor disorders is unknown. 

They developed an intravaginal pressure sensor to measure intraabdominal pressure. They will 

perfect the wireless technology needed to use the sensor remotely so that they can understand 

how different activities done during real world settings affect intraabdominal pressures and 

pelvic floor disorders. Pelvic floor disorders affect one in four American women. Few 

modifiable risk factors have been identified that might reduce the incidence or progression of 

pelvic floor disorders. Popular wisdom and scant clinical data suggest that strenuous activity 

causes or promotes pelvic floor disorders. Given the health benefits of activity, women should be 

encouraged to be maximally active unless there is scientific evidence to the contrary. Existing 

physical activity instruments are largely designed to assess cardiovascular exertion and are 

validated using activity diaries, accelerometers, and step counters. Such measures may not 

accurately measure activities that increase loading on the pelvic floor (such as lifting). After 

researching available technologies, they concluded that a tool to understand how physical 

activities impact abdominal pressure in the real world does not exist. Over the past 18 months, 

their interdisciplinary team of bioengineers, urogynecologists, electrical engineers, and exercise 

scientists developed and validated the performance of a prototype for an intravaginal abdominal 

pressure sensor that accurately measures pressure in the upper vagina, an easily accessible space 

that records pressures similar to the true intraabdominal pressure. In this proposal, they plan first 

to further develop an integrated system (the "WRAPS", Wireless Remote Abdominal Pressure 

System) to monitor intraabdominal pressure outside of the clinical setting. This system will 

consist of three key elements: an intravaginal pressure sensor with wireless data transmission 

capability, a small portable data monitoring and storage unit, and computer based data translation 

software for downloading and managing the pressure data. In a controlled exercise laboratory 

setting, they will then use intraabdominal pressure data generated by the WRAPS to determine 

the reproducibility of intraabdominal pressures measured during specific types of physical 

activity and will finalize development of a valid questionnaire that categorizes the magnitude of 

intraabdominal pressures during activities. Finally, in a real-world setting in which participants 

wear the intravaginal sensor during waking hours for four 1-week periods over the course of a 

year, they will characterize intraabdominal pressures experienced by women of varying degrees 

of habitual physical activity and, using WRAPS data as the gold standard, determine whether 

activity can be appropriately categorized in terms of pelvic loading by means of self-
125

administered questionnaires, the current standard. Obtaining future evidence about the impact of 

physical stressors on pelvic floor disorders relies on their ability to measure the risk factor in 

question. This innovative translational collaboration will remove a critical barrier to progress in 

understanding the etiology of pelvic floor disorders in women. 

1-R21-HD-065138-01A1

Molecular Basis of Treating Endometriosis by Prostaglandin E2 Receptor Inhibitors

Arosh, Joe A

Texas A&M University

$200,000

The objective of the proposed research is to determine molecular and cellular mechanisms 

through which selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits 

survival of endometriosis in order to identify PGE2 as potential nonestrogen or nonsteroidal 

target for the treatment of endometriosis in women. The expected outcomes of this project are 

that selective inhibition of EP2 and EP4-mediated PGE2 signaling will: (i) inhibit survival of 

endometriosis through suppressed cell survival and activated intrinsic apoptotic pathways; (ii) 

increase phagocytic ability of infiltrated peritoneal macrophages around endometriosis per se; 

(iii) inhibit local estrogen production in endometriosis; and (iv) provide exciting new knowledge 

that fill the gap in understanding of the pathogenesis of endometriosis. The novel findings of this 

project are expected to establish potential translational opportunities for treatment of 

endometriosis by blocking EP2 and EP4 receptors and could emerge as potential nonestrogen or 

nonsteroidal therapy for endometriosis in child- bearing age women. Endometriosis is an 

estrogen dependent disease. Current medical therapies to inhibit estrogen biosynthesis and 

actions fail to prevent reoccurrence of the disease and compromise success of pregnancy in 

child-bearing age women. This suggests a crucial need to identify potential cell signaling 

pathways for nonestrogen therapeutic targets for endometriosis. Prostaglandin E2 (PGE2) 

promotes survival of endometriosis, however; the underlined molecular mechanisms are largely 

unknown. Our long-term goal is to understand molecular and cellular aspects of PGE2 

biosynthesis and signaling cross-talk in the pathogenesis of endometriosis in order to identify 

new targeted therapies. The objective of this application is to understand PGE2 signaling 

pathways in survival and growth of endometriosis. Our central hypothesis is that loss-of-function 

of PGE2 receptors EP2 and EP4 inhibits survival and growth of endometriosis. Specific Aim-1 

will determine the mechanisms through which loss-of-function of EP2 and EP4 induces 

apoptosis of endometriosis. Specific Aim- 2 will determine the mechanisms through which EP2 

and EP4-mediated PGE2 signaling immunomodulate and enhance the phagocytic ability of 

macrophages in endometriosis. Specific Aim-3 will determine the mechanisms through which 

loss-of-function of EP2 and EP4 decrease estrogen production in endometriosis. Our 

experimental approaches include: (i) genomic and pharmacological inhibition of EP2 and EP4; 

(ii) stable fluorescence-labeled human endometriotic epithelial cells, stromal cells, macrophages, 

and eutopic and ectopic endometria from endometriosis patients, (iii) nude and Rag2g(c) mice 

xenograft models, (v) molecular, cellular, biochemical, and microscopy-based assays; and (vi) 

whole animal bioimaging method. The rationale is that successful completion of the proposed 

research will contribute a missing and fundamental element to our base of knowledge without 

which the mechanism through which selective inhibition of EP2 and EP4 induces apoptosis of 
126

human endometriotic cells cannot be understood. In addition, the expected results will advance 

the current knowledge of the pathogenesis of endometriosis and increase the understanding of 

PGE2 signaling in survival of endometriosis. The acquisition of such knowledge is critical and 

could be translated to treat women suffering from endometriosis. It is our expectation that 

selective inhibition of EP2 and EP4 will induce apoptosis of endometriotic cells, increase 

phagocytic ability of infiltrated macrophages in endometriosis per se, and decrease estrogen 

production by the endometriotic cells through multiple mechanisms. Our findings would have 

clinical impact because it would allow for the first time to develop new and much needed 

therapeutic strategies to inhibit EP2 and EP4 signaling as novel nonestrogen targets for the 

treatment of endometriosis in child-bearing age women. This is a R21 application addresses the 

mission of NIH/NICHD on women's reproductive health. 

1-R21-HD-069165-01A1

Novel Approaches For Disrupting Gene Expression In Mammalian Oocytes

Evans, Janice P

Johns Hopkins University

$200,000

Investigations of the biology of the mammalian oocyte are of significant value, both for 

increasing our basic biological knowledge and for applications to human reproductive health. 

This project will accelerate the pace of research in this important area of reproductive health by 

developing new research methods for use in studying oocyte biology and female fertility and 

infertility, and for development of new female contraceptive methods. This R21 project seeks to 

develop new approaches for the genetic manipulation of mammalian oocytes, which we envision 

will accelerate advancing our knowledge of oocyte function and reproductive health. Genetic 

manipulation of mammalian oocytes has primarily used two methods: RNA interference and 

knockout mice. While RNAi has been a highly successful method of RNA ablation and 

subsequent protein knockdown in oocytes, RNAi approaches are not without limitations, as 

knockdown can be inefficient. Furthermore, double-stranded RNA and siRNAs have to be 

introduced into oocytes by microinjection, which is labor- and time-intensive and makes it 

impractical do use a large-scale RNAi approach (e.g., siRNA library-based screens). Knockout 

mice certainly have provided significant insights into mammalian oocyte biology as well, but 

knockout approaches also are not without pitfalls, including the time and expense involved in 

obtaining a knockout. This project seeks to develop alternatives to these methods, utilizing 

different established nucleic acid-based methods in novel combinations and with specialized 

modifications for the applications proposed here. In Aim 1, we will augment the use of siRNAs 

for post-transcriptional gene silencing with another reagent, a short single-stranded nucleic acid 

called a triplex-forming oligonucleotide (TFO) for pre-transcriptional silencing. TFOs bind to 

homopurine tracts in double-stranded DNA, and have been used to regulate gene expression in 

cultured cells and in vivo. The hypothesis for Aim 1 is that TFOs will inhibit transcription of a 

targeted gene, while siRNAs will mediate degradation of any residual mRNAs that were 

transcribed. This will be tested in vitro with isolated oocytes as well as with follicle-enclosed 

oocytes for longer-term culture. In Aim 2, we will develop methods for delivery of agents into 

oocytes. We will identify a novel agent for oocyte- specific delivery, using a screen of an 

aptamer library (with 1.2 X 1018 oligo-2'-deoxyribonucleotide sequence isomers) to isolate an 
127

aptamer that will interact with the oocyte's zona pellucida (ZP). Aptamers are nucleic acid-based 

molecules that bind with high affinity to target molecules. Aptamers can be used for delivery of 

agents such as siRNAs into cells; this delivery works in vivo, and aptamers currently are being 

developed as therapeutics to target drugs and other agents to specific cell types for treatment of a 

variety of diseases (13 aptamers are in clinical trials). Additionally, as an alternative tool, we will 

also test a cell-penetrating peptide for intra-oocyte delivery. We will couple siRNAs or TFOs to 

ZP-binding aptamers and/or a cell-penetrating peptide, and test these for their actions in oocytes. 

The future direction of this work will be to test the ZP-targeting aptamer for systemic delivery of 

siRNAs and TFOs, as a means of in vivo oocyte-specific knockdown as an alternative to 

knockout/transgenic methodologies, as well as potentially the foundation of a novel female 

contraceptive. 

1-R03-HD-067413-01

Phospholipid-reactive T cells in Pregnancy Loss

Halder, Ramesh C.

University Of California Los Angeles

$77,000

Pregnancy loss is a major unsolved complication of many autoimmune diseases. The proposed 

studies will investigate a new mechanism of pathogenesis of autoimmune-mediated pregnancy 

loss and improve our understanding of the role of certain T cells in the development of 

autoimmune pregnancy loss. Recurrent pregnancy loss is associated with the presence of 

autoantibodies against phospholipid (PL) antigens in some patients. Mechanisms underlying the 

development of such autoimmune pregnancy loss are not well understood. Recent reports have 

suggested existence of T cells that recognize PL antigens bound to an antigen presenting 

molecule, CD1d. My hypothesis is that such CD1d-restricted PL-reactive T cells induce the 

production of anti-PL autoantibodies and pregnancy loss associated with these antibodies. In 

support of this hypothesis, we have found that CD1d-knockout autoimmune-prone (NZB X 

NZW) F1 mice have significantly reduced serum levels of anti-PL antibodies as compared to 

their wild-type littermates, suggesting a possible role of CD1d in the development of anti-PL 

antibodies. Building on my expertise in the biology of CD1d-restricted glycolipid-reactive T 

cells and based on the above observations, I will test this hypothesis in three Specific Aims. In 

Aim 1, I'll test the hypotheses that mice with spontaneous or induced anti-PL antibodies have 

increased numbers and/or activation of PL-reactive T cells in lymphoid organs; such T cells will 

infiltrate the pregnant uterine mucosa, called decidua, in increased numbers. Then, I'll determine 

the effect of CD1d-restricted PL-reactive T cells on the production of anti-PL antibodies by B 

cells in vitro in Aim 2. In Aim 3, I'll determine the effect of CD1d-restricted PL-reactive T cells 

on pregnancy outcome. We will further investigate whether PL-reactive T cells directly induce 

pregnancy loss or whether pregnancy loss is mediated via anti-PL antibodies induced by PLreactive T cells. It is hoped that this study will elucidate a novel pathogenetic mechanism of 

recurrent pregnancy loss in autoimmune diseases. The data obtained will also form the basis for 

my first R01 or another extramural proposal. 

1-R01-HD-065939-01A1

Molecular Mechanism Of LPA3-Mediated Uterine Receptivity
128

Ye, Xiaoqin

University Of Georgia

$200,000

The proposed research is relevant to public health because defective uterine receptivity is a key 

factor for two important public health problems, infertility and early pregnancy loss. This 

proposal aims to decipher how a local factor LPA3 interplays with progesterone receptor in 

uterine luminal epithelium to control uterine receptivity. The understanding of the molecular 

mechanism in establishment of uterine receptivity will provide the foundation for drug 

discoveries to treat infertility and early pregnancy loss associated with defective uterine 

receptivity. Defective uterine receptivity, including delayed uterine receptivity and nonreceptive endometrium, is the key maternal factor for infertility and early pregnancy loss. The 

molecular mechanism of how a uterus transforms into a receptive state for embryo implantation 

is not well understood. It is well recognized that progesterone receptor (PR)-mediated hormonal 

signaling is essential for the establishment of uterine receptivity in all mammals studied. PR has 

dynamic spatiotemporal expression patterns in the peri-implantation uterus. The disappearance 

of PR from uterine luminal (LE) and glandular epithelium is associated with the establishment of 

uterine receptivity. Failure of such down regulation of PR in uterine epithelium during the 

expected "implantation window" is associated with defective uterine receptivity. LPA3 

(LPAR3/EDG7) is the third receptor for lysophosphatidic acid. Down regulation of uterine LPA3 

is implicated in defective uterine receptivity in endometriosis patients and deletion of Lpar3 in 

mice leads to delayed uterine receptivity. Sustained PR expression in LE is detected in the nonreceptive day 4.5 Lpar3(-/-) mouse uterus (normal implantation: ~day 4.0 in mouse). How the 

sustained PR expression in LE during the expected "implantation window" blocks uterine 

receptivity and how PR-mediated hormonal signaling interacts with local targets to control 

uterine receptivity remain as significant knowledge gaps. The long-term goal is to understand the 

molecular mechanism of uterine receptivity thus help overcome infertility and early pregnancy 

loss associated with defective uterine receptivity. The overall objective of this application is to 

fill the mentioned knowledge gaps, specifically the significance of sustained PR expression in 

LE and the interplay between PR and LPA3 in LE. The central hypothesis, formulated based on 

supportive preliminary data, is that PR interplays with LPA3 to coordinately regulate uterine 

receptivity. The rationale is that understanding the significance of PR in LE and its interplay with 

LPA3 will provide more insight into the molecular mechanism of uterine receptivity. To achieve 

the goal of this application, three specific aims will be pursed. Aim 1. Determine molecular 

pathways dysregulated in LE with sustained PR expression, based on the working hypothesis that 

sustained PR expression in LE dysregulates genes/molecular pathways leading to a non-receptive 

uterus. Aim 2. Determine interplay between PR and LPA3 in LE, based on the working hypothesis that PR and LPA3 mutually regulate each other in LE for the establishment of uterine 

receptivity. Aim 3. Determine role of LPA3 in regulating molecular pathways in preimplantation 

day 3. 5 endometrium, based on the working hypothesis that LPA3 regulates its uterine target 

genes to influence uterine receptivity directly and/or via PR in LE. Laser microdissection, gene 

profiling, immunoblotting, ChIP assay, and immonoprecipitation are among the approaches that 

will be employed. The proposed work is significant because understanding the molecular 

mechanism of uterine receptivity is critical for developing diagnostic and therapeutic approaches 
129

to detect and treat infertility and early pregnancy loss associated with defective uterine 

receptivity. 

5-P01-HD-057877-03

Uterine Leiomyoma Research Center Program

Bulun, Serdar E.

Northwestern University

$250,000

Symptomatic uterine leiomyomata affect millions of US women and cause irregular uterine 

bleeding, anemia, recurrent pregnancy loss leading to more than 200,000 hysterectomies per 

year. Available treatments are limited due in large part to the fact that the mechanisms regulating 

the development and growth of these tumors are unclear. They propose integrated molecular, 

cellular and translational studies that should lead to a better understanding and future 

development of novel therapeutics for uterine leiomyomata. Uterine leiomyomata (fibroids) 

represent the most prevalent benign gynecologic disorder in the US. The cellular and molecular 

mechanisms regulating the development and growth of leiomyoma are not well understood. 

Their multidisciplinary team has designed 3 well-integrated projects focusing on Interactions 

between biologically critical hormonal pathways in uterine leiomyoma involving the 

transcription factors progesterone receptor (PR) and FOXO, the signaling pathway PI3K/AKT 

and the pro-fibrotic factor TGF-beta. Project I (Bulun) will be pursued to understand the 

mechanisms as to how antl-progestins such as RU486 reduce tumor size. They hypothesize that 

progesterone regulates a number of critical genes, that favors increased proliferation and 

decreased apoptosis of leiomyoma smooth muscle cells, whereas anti-progestins reverse this 

effect by enhancing apoptosis and decreasing proliferation. Project II (Kim/Chakravarti) will 

determine the role of the PI3K/AKT/F0X0 signaling pathway regulating leiomyoma cell growth 

and survival in response to progesterone. They hypothesize that progesterone Induces 

proliferation of leiomyoma cells through activation of the PI3K/AKT/F0X0 signaling pathway 

and that Inhibitors of the AKT pathway should override the proliferative effects of progesterone 

and promote apoptosis. Project III (Nowak) will define the mechanisms as to how antifibrotic 

drugs regulate leiomyoma growth. They hypothesize that the increased proliferation exhibited by 

leiomyoma smooth muscle cells Is due to a major shift in the extracellular matrix environment 

caused by increased synthesis of new, monomeric collagen type I by these cells. They will 

determine whether antifibrotic drugs may be an effective new treatment for leiomyomas. These 

projects are supported by an Administrative Core (Bulun) and Tissue Procurement and Cell 

Culture Core (Kurita). Overall, as part of their long range goal, all projects investigate local 

hormonal signaling regulating apoptosis and proliferation as biologic endpoints and test existing 

and upcoming pharmaceutical compounds that target these pathways in uterine leiomyomata. 

1-S06-GM-092238-01

Oklahoma Native American Research Centers for Health (NARCH VI)

Grim, Gloria Ann

Cherokee Nation
130

$100,000

The purposes of this project are: to encourage competitive research linked to reducing health 

disparities; to increase the capacity of the Tribes and University of Oklahoma to work in 

partnership to reduce distrust by the Native American communities and peoples toward research; 

and to develop a cadre of Native American scientists and health professionals engaged in 

biomedical, clinical and behavioral research that is competitive for NIH funding. The sixth 

Oklahoma Native American Research Center for Health (0NARCH6) continues the productive 

research and training partnership with the University of Oklahoma Health Sciences Center 

(OUHSC) by the Tribes, especially the Chickasaw, Creek, Choctaw and Cherokee Nations. 

Population served consists of 42,749 Chickasaws and 121,680 Cherokees, 49,714 Choctaws and 

30,181 Creeks for a total of 244,324 in North East and South Central Oklahoma. The research 

will include 1) the impact of infections on maternal and child health in Native Americans, 2) 

research to develop better diagnostic and prognostic tests for rheumatic disease in Oklahoma 

tribal members, and to examine the potential roles of environmental triggers for autoimmunity 

focusing on vitamin D levels, tobacco smoke exposure (through serum cotinine levels) and 

abnormal immune responses to common viruses, 3) research to prevent excessive gestational 

weight gain in otherwise healthy but overweight Native American women and consequently 

decrease the proportion of women who gain in excess of the guidelines has the potential to 

decrease the risk and costs of obstetric complications associated with excessive weight gain, and 

4) to develop methods to understand attitudes, beliefs, and perceived barriers or motivators to 

organ/tissue donation among American Indians living off-reservation.

5-S06-GM087165-02

Research to Improve Preconception Health of Adolescent Women (NARCH VI)

Jumping Eagle, Sara

Oglala Lakota Oyate

$128,436

The Oglala Sioux Tribe, in partnership with Stanford Research/University of South Dakota 

School of Medicine and the Oglala Lakota College, will be addressing priority health issues 

identified by the tribe and to support and expand the research capacity and infrastructure that will 

build on the research foundation that has been developed within the tribe over the past decade.

Z01-HD008737-11

ORWH-NICHD Leiomyoma Tissue Bank

Segars, James

NICHD Intramural program

$50,000

The health of 30-50% of women in the U.S. is adversely affected by uterine leiomyoma 

(fibroids). Uterine fibroids are a health disparity issue that disproportionately affects African 

American women. Research into causes and treatment has lagged behind other disciplines, in 

part due to lack of available tissues, since surgical samples are often not made available to 

scientists. To address the problem of tissue availability, and promote research on this condition, 

this project proposes to establish a fibroid tissue bank as an initiative in the intramural program 
131

of NICHD. This tissue bank will provide samples to NIH-funded investigators and DoD-funded 

investigators to support work on this condition. The Leiomyoma Tissue Bank (LTB) will be 

physically located in space assigned to Dr. Segars of NICHD. The LTB will be structured after 

RStaR-banks for endometrium and ovary established by the Specialized Cooperative Program in 

Reproductive Research. Computerization of sample inventory will be performed with software 

provided by NICHD.

1-R21-HD-066248-01A1

Prostaglandin E2 Signaling in Growth and Pains of Endometriosis

Arosh, Joe A

Texas A&M University

$ (NICHD funded this ANSWHR award)

The objectives of the proposed research are to determine molecular and cellular mechanisms 

through which selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits 

growth of endometriosis and endometriosis-induced pain and to develop EP2 and EP4 inhibitors 

as new non-steroidal targets for the treatment of endometriosis in women. The expected 

outcomes of this project are that selective inhibition of EP2 and EP4-mediated PGE2 signaling 

will decrease growth and pain of endometriosis and fill the substantial gap in the current 

knowledge of the pathogenesis of endometriosis and perception of endometriosis pain. This 

highly significant advancement in our understanding of endometriosis will provide the 

knowledge needed to translate selective inhibition of EP2 and EP4 into clinical application as a 

potential novel non-steroidal therapy for endometriosis in women. Endometriosis is an 

inflammatory disease characterized by the presence of functional endometrium outside the 

uterine cavity. The major two symptoms are intolerable pelvic pain and infertility. Prostaglandin 

E2 (PGE2) plays important roles in the pathogenesis of endometriosis. PGE2 is the principal 

mediator in inflammation and pain hypersensitivity. Inhibition of PGE2 biosynthesis using 

NSAIDs and COX-2 inhibitors has emerged as the main class analgesics. However, clinical use 

of NSAIDs produces unwanted side effects such as gastric erosion, ulceration, and hemorrhage, 

and prolonged use of COX-2-selective inhibitors confers a risk for myocardial infarction and 

stroke. PGE2 produced at the site of inflammation acts on the nociceptors of peripheral terminals 

through EP1, EP2, EP3, and EP4 receptors by integrating multiple cell signaling pathways. 

Selective inhibition of PGE2 signaling as therapeutic targets down-stream of COX-2 may 

provide an opportunity to inhibit pro-nociceptive actions of PGE2 in the pathogenesis of 

endometriosis. Our long-term goal is to understand molecular and cellular aspects of PGE2 in the 

pathogenesis and pain of endometriosis with the aim of identifying PGE2receptors as nonsteroidal targets for the treatment of endometriosis. The objective of this application is to 

understand PGE2 signaling in growth and pain of endometriosis. The central hypothesis is that 

selective inhibition of prostaglandin E2 signaling decreases pain of endometriosis through 

inhibition of growth of endometriotic cells and development of nociceptive mechanisms. 

Specific Aim 1 will determine the effects of systemic blockade of EP2 and EP4 receptors on 

growth, innervations, and pain of endometriosis. Specific Aim-2 will determine molecular 

mechanisms of through which cell specific knock-down of EP2 and EP4 in endometriotic 

epithelial and stromal cells inhibits development of innervations and nociceptive mechanisms of 

endometriosis. Effects of selective inhibition of EP2 and EP4 on growth, innervations, and pain 
132

of endometriosis will be determined using genomic, pharmacological, molecular, cellular, 

biochemical, microscopy, and bioimaging approaches, and xenograft Rag23(c) mice and pain 

behavior animal models. The proposed work is innovative: (i) because it capitalizes on a new 

means of identifying PGE2 signaling in the pathogenesis of endometriosis and induction of 

endometriosis pain, and (ii) expected to decrease pain of endometriosis through inhibition of 

growth of endometriotic cells, innervations of endometriosis, and development of peripheral and 

central nociceptive mechanisms. This highly significant advancement in our understanding of 

endometriosis will provide the knowledge needed to translate selective inhibition of EP2 and 

EP4 into clinical application as a potential novel non-steroidal therapy for endometriosis in 

women. In addition, the expected results will fill the substantial gap in the current knowledge of 

the pathogenesis of endometriosis and perception of endometriosis pain. This is a R21 

application addresses the mission of NIH/NICHD on women's reproduction health. 

1-R21-AI-095987-01

Vitamin D And The Prevalence, Incidence, And Persistence Of Bacterial Vaginosis

Norris Turner, Abigail

The Ohio State University

$ (NIAID funded this ANSWHR award)

Bacterial vaginosis is the most common vaginal infection in women of reproductive age 

worldwide. We hypothesize that low vitamin D levels contribute to increased risk of bacterial 

vaginosis. This study will test stored, prospectively-collected biological samples and use existing 

demographic, behavioral and clinical information from almost 600 Zimbabwean women to 

assess the influence of vitamin D on the prevalence, incidence and persistence of bacterial 

vaginosis. Bacterial vaginosis (BV) is a vaginal condition that develops when the concentration 

of healthy Lactobacillus species in the vagina declines and is replaced by other (largely 

anaerobic) bacterial species. BV is the most common vaginal infection worldwide in women of 

reproductive age. Pregnant women with BV have increased risks of spontaneous abortion, 

preterm labor, preterm birth, chorioamnionitis and other detrimental obstetric and gynecologic 

outcomes. According to a recent meta-analysis of more than 30,000 women, prevalent BV was 

associated with a 60% increased risk of acquisition of human immunodeficiency virus (HIV). 

However, the etiology of this complex condition is not clear. We hypothesize that low vitamin D 

levels contribute to BV pathogenesis. Vitamin D is essential to immune function, serving both to 

stimulate mechanisms associated with pathogen elimination and to regulate immune response. In 

the United States (US), the strongest risk factor for BV is non-white race, and non-white women 

are also much more likely to have insufficient or deficient vitamin D levels. Indeed, two recent 

cross-sectional analyses report that vitamin D insufficiency is associated with prevalent BV in 

pregnant African-American women; a third publication found the same association between 

vitamin D and BV in a nationally-representative population of pregnant women including all 

racial/ethnic categorizations. These data suggest that the consistent association between race and 

BV (despite adjustment for other BV risk factors) may be mediated by vitamin D. Little data 

exist on vitamin D levels in resource-limited settings, including sub-Saharan Africa where BV 

prevalence is high and BV- associated morbidities are substantial. Using stored serum samples 

from nearly 600 Zimbabwean women who previously participated in the prospective, 

observational "Hormonal Contraception and Risk of HIV Acquisition" (HC-HIV) study, we 
133

propose to measure the association between serum vitamin D levels and a) BV prevalence; b) 

BV incidence; and c) BV persistence. In an exploratory analysis using stored cervical and serum 

samples from a subgroup of 50 BV-positive and 50 BV-negative women, we will also evaluate 

correlations between BV-associated cervical immunoinflammatory mediators and vitamin Dassociated serum immunoinflammatory mediators to elucidate the possible immunological 

mechanisms through which vitamin D may affect BV. Vitamin D is safe, inexpensive and has 

many health benefits. If vitamin D is also associated with BV, supplementation with this 

essential vitamin may have substantial impact on women's reproductive health worldwide. 

1-R21-HD-068873-01A1

A Longitudinal Study Of Loss Of Imprinting In First Trimester CVS Samples Compared 

To Placental Samples At Birth

Lee, Men-Jean

Indiana University

$273,068

We have novel preliminary data to suggest that genomic imprinting in the human placenta takes 

place across gestation and is not permanently fixed in early pregnancy. We seek to confirm this 

finding in a longitudinal study of loss of imprinting by monitoring placenta samples from 

chorionic villus sampling in the first trimester and the same respective placentas at birth. We will 

also explore how differences in loss of imprinting patterns in first trimester placenta samples 

may be predictive of pregnancy complications which can ultimately be developed into a bioassay 

for adverse pregnancy outcomes. For most human genes, maternal and paternal alleles are biallelically expressed. However, a specific subset of genes are imprinted and mono-allelically 

expressed. The current dogma is that this embryonic imprint is stable across the lifespan of the 

organism. Loss of imprinting (LOI) leads to bi-allelic expression of the imprinted gene, 

potentially causing a doubling of gene dosage or gene dysregulation, resulting in disease. 

Because the methylation marks of imprinted genes are considered permanent after fertilization, 

any acquired changes in the intrauterine environment may lead to stable transgenerational 

effects. The regulatory complexity of these imprinted gene domains may render them 

particularly sensitive to environmental changes such as diet and nutrition. Emerging evidence 

implicates aberrant imprinting in the pathophysiology of many common human diseases, 

including complications of pregnancy such as intrauterine growth restriction (IUGR) and 

preeclampsia (PE); and even postnatal disorders such as obesity, cardiovascular disease, and type 

2 diabetes. We have developed a highly sensitive and quantitative allele-specific PCR analysis to 

measure LOI in a panel of imprinted genes in the human genome. Using this methodology, we 

have already determined that pregnancies complicated by PE and IUGR are associated with 

dysregulation of a set of imprinted genes in the placenta. Both of these obstetrical disorders have 

their origins in an early intrauterine environment associated with aberrant placentation and 

trophoblast invasion. We also have novel evidence to suggest that genomic imprinting patterns 

are not permanently fixed in placental development. Contrary to the prevailing theory, we 

hypothesize that patterns of LOI are not static in the human placenta and are subject to 

developmental and environmental influences over the course of pregnancy that predispose to 

adverse pregnancy outcome. We now propose a longitudinal trial as a secondary study to the 

NuMOM2B Trial to monitor LOI in placenta samples from first trimester CVS to birth and 
134

determine which LOI patterns in the first trimester lead to normal pregnancy outcomes and 

which patterns are predictive of pregnancy complications. 

1-U10-HD-069010-01

Pelvic Floor Disorders Network Clinical Sites 

Arya, Lily A

University Of Pennsylvania

$25,000

The University of Pennsylvania has the expertise, infrastructure and experience to be a 

significant contributor to the Pelvic Floor Disorders Network. The proposed study, to investigate 

the efficacy of a new treatment for urge urinary incontinance, will improve quality of life of 

women with urge incontinence and result in considerable savings of health care resources. The 

goal of this application is to competitively identify clinical sites to conduct clinical trials for 

female pelvic floor disorders. This application from the University of Pennsylvania with Lily 

Arya MD, MS (Epidemiology) as Principal Investigator demonstrates our research plan for a 

new treatment for urge urinary incontinence, myofascial physical therapy. This potentially 

effective and safe method will greatly enhance treatment choice and improve the quality of life 

of women with urge urinary incontinence. This application outlines our extensive experience 

with similar large multi-center clinical trials. We highlight our ability to recruit and maintain 

subjects in female pelvic floor disorder clinical trials, noting we have been one of the leading 

recruitment centers in the nation for similar trials. We have often been able to recruit a greater 

number of subjects than our original estimates. The facilities at the University of Pennsylvania 

are supportive and outstanding. Our existing research unit and personnel has continuously 

demonstrated highly successful management of large clinical trials with outstanding 

organization, attention to detail and compliance with Good Clinical Practice, federal regulations 

and local Institutional Review Boards. Dr. Arya is an active researcher in the field of health 

measurement for pelvic floor disorders and she has successfully conducted a number of clinical 

trials in women's health. Specifically, she and her team of co- investigators and staff have been 

actively involved in surgical and non-surgical trials for urinary incontinence. She will bring 

significant expertise regarding study design and health measurement research to the Pelvic Floor 

Disorders Network. She leads a team of co-investigators who have a track record of collaborative 

clinical and translational research. We feel that the combination of a high quality personnel, 

experience in the research area, ability to recruit, and outstanding management and organization 

will contribute to a high likelihood of successful completion of this and future trials of treatment 

methods of pelvic floor disorders. 

2-U10-HD-054215-06

Cleveland Clinic Clinical Site

Barber, Matthew 

Cleveland Clinic Lerner Col/Med-CWRU
135

$25,000

Nearly one quarter of all women report symptoms of at least one PFD, including prolapse. POP 

is the most common indication for hysterectomy in postmenopausal women and it is unknown 

whether the addition of hysterectomy to POP surgery is integral to successful surgical outcome. 

The results of our concept proposal could justify or eliminate the need for as many as 70,000 

hysterectomies in the US each year. The goal of the Pelvic Floor Disorders Network (PFDN) is 

to identify optimum diagnosis and management strategies for women with pelvic floor disorders 

(PFD) using the highest quality research methods available. The Cleveland Clinic offers a stable 

academic and research-oriented environment for the conduct of PFDN studies including 

experienced investigators with complementary clinical and research backgrounds that have a 

particular interest and a successful history of conducting clinical trials evaluating both surgical 

and nonsurgical therapies for women with PFD. The specific aims of this application are: 1) to 

demonstrate that the Cleveland Clinic (CC) Clinical Site has contributed substantially to the 

academic, administrative, and clinical aspects of the PFDN since joining in its 2nd 5-year cycle; 

that it possesses the personnel, patient, clinical and administrative resources needed for 

successful participation; and that continued participation would be advantageous to the 

successful attainment of the Network's scientific goals and 2) to present a concept proposal for 

potential conduct by the PFDN. We propose evaluating the comparative effectiveness of 

sacrospinous hysteropexy (SSH), the most well-studied uterine-sparing pelvic organ prolapse 

(POP) surgery, relative to total vaginal hysterectomy with sacrospinous ligament fixation 

(TVH/SSLF), a commonly used hysterectomy-based vaginal uterovaginal prolapse procedure. 

The specific aims of the concept proposal are: 1) compare the anatomic, functional, sexual and 

health-related quality of life outcomes of SSH to TVH/SSLF in women undergoing surgery for 

Stage 2-4 POP uterovaginal prolapse 2 years after surgery; 2) compare surgical recovery and 

short- and long-term morbidity of SSH and TVH/SSLF in these same women and 3) determine 

the incremental cost-effectiveness of SSH compared to TVH/SSLF for the treatment of Stage 2-4 

POP. Enrolled subjects will be randomized in the operating room on the day of surgery to 

receive either SSH or TVH/SSLF (1:1) using a random permutated block design. Randomization 

will be stratified by surgeon to account for the varying experience and expertise. Subjects and 

study coordinators will be blinded to treatment assignment until completion of the study. 

1-U10-HD-069013-01

Brown/WIH Pelvic Floor Disorders Network Site

Myers, Deborah Lee

Women And Infants Hospital-Rhode Island

$25,000

Female pelvic floor disorders including urinary incontinence, pelvic organ prolapse and fecal 

incontinence are common, disabling conditions and are a significant public health issue. 

Although a variety of treatment options exist, high quality evidence to guide clinical 

management and to improve treatment specificity is still needed. Through the PFDN, 

WIH/Brown is committed to advancing high quality scientific evidence to help improve the care 

of women and reduce the burden of these disorders. The mission of the PFDN is to identify 

optimal diagnosis and management strategies for women with pelvic floor disorders (PFDs) and 
136

this is directly in line with Women and Infants Hospital (WIH)/Brown's mission and 

commitment. WIH is a women's hospital, focused solely on advancing women's health and 

research and our extremely high volume, stable patient base, expertise of our multi-disciplinary 

collaborative and established research infrastructure provide the ideal environment to conduct 

large-scale, clinical research at the highest level. The aim of this application is for WIH/Brown 

to become the first PFDN site in New England by demonstrating: 1)our academic productivity 

and experience in multi-site, collaborative surgical, pharmaceutical and non-surgical clinical 

trials; 2)highly committed investigators with expertise in research methods and a specialized 

research team qualified to conduct multiple protocols, manage high quality data, and maintain 

high recruitment and retention; 3)a long-standing, formal relationship with multi-disciplinary 

collaborators committed to advancing the care of women with PFDs led by Urogynecology 

(including Urology, Colorectal surgery, Women's Gastroenterology, Women's Physical Therapy, 

and Women's Radiology); and 4)our high clinical volume (In 2009, the Division of 

Urogynecology evaluated 1211 new patients and performed 583 PFD surgical procedures; 

vaginal, abdominal, laparoscopic and robotic approaches are all represented). We present a 

concept proposal describing a 3-stage, randomized trial of a combined non-surgical and surgical 

approach to treatment of mixed urinary incontinence (MUl) in women who have failed 

conservative therapy and/or elect surgical treatment. Women suffering from MUl are at high risk 

for failure of segregated treatments and are often excluded from clinical trials focused on either 

stress or urge urinary incontinence alone. Clinical management of MUl remains a challenge and 

trials targeting this population are urgently needed. WIH has a long-standing history of 

supporting network collaboratives and our goal is to participate and become a leader in the 

PFDN in terms of protocol development and completion, data interpretation and quality, 

recruitment and retention and high quality dissemination of findings. 

2-U10-HD-054214-06

Pelvic Floor Disorders Network

Nager, Charles William

University Of California San Diego

$25,000

Our site's participation in the next cycle of the PFDN should allow successful network 

recruitment for surgical trials. Uterine prolapse is a very common pelvic floor disorder and we 

should determine the best vaginal surgical treatment for this condition. This proposed research 

study will answer whether uterine - sparing procedures are reasonable alternatives to 

hysterectomy for this condition. The objectives and aims of this application are for the San 

Diego site to continue its work In the Pelvic Floor Disorders Network (PFDN). The unique 

strength of our application is our proven two site model, which combines the strengths of 7 

academic investigators at both a tertiary medical center and a large volume HMO. We would like 

to provide leadership, continuity, innovation, academic expertise, a captured diverse patient 

population, and a proven research infrastructure to the network. We have a track-record of being 

the top 2 recruitment in surgical trials for pelvic floor disorders and we want to continue that into 

the third cycle of the PFDN. As noted in the RFA," In many cases, clinicians caring for women 

with pelvic floor disorders have adopted principles of care and surgical techniques before 

rigorous, objective, controlled evaluation has taken place. New devices and techniques have had 
137

a dramatic influence on surgical practice...".Our study addresses this concern. Vaginal mesh is 

probably the most controversial topic in pelvic floor disorders and a strong argument can be 

made that the PFDN is the best group to study it. A growing-trend of women is seeking uterine 

sparing surgery for prolapse and a growing trend of gynecologists and urologists are managing 

uterine prolapse with vaginal mesh kit procedures. Our proposed randomized trial of uterine 

sparing, grafted vaginal apical suspension vs. traditional hysterectomy with native tissue 

suspension addresses the very important question of whether it is necessary to remove the uterus 

to treat uterine prolapse. This proposed study recognizes the role of new devices and techniques 

that are changing our care of women with pelvic floor disorders. Our comprehensive outcome 

measures should allow us to answer whether these new uterine-sparing, apical vaginal 

procedures are reasonable alternatives to conventional vaginal hysterectomy and native tissue 

suspension. 

2-U10-HD-041261-11

Perioperative Pelvic Floor Rehab: A Randomized Trial

Richter, Holly E

University Of Alabama At Birmingham

$25,000

In order to improve on the care and individualized treatment for women with pelvic floor 

disorders, it is important that a credible research program exists that helps guide provider care. 

The Pelvic Floor Disorders Network (NICHD) performs such research and we are competing to 

continue to participate in this important initiative. As a part of this application, we propose a 

concept describing a randomized trial of sacral neuromodulation for the treatment of women 

with fecal incontinence refractory to current standard of care treatments. This exciting new 

treatment modality may help a cohort of women with diminished quality of life. The University 

of Alabama at Birmingham (UAB) is seeking to successfully compete in the third cycle of the 

NICHD sponsored Pelvic Floor Disorders Network. As a part of this important research 

infrastructure we have demonstrated our credible, productive, multidisciplinary clinical approach 

to the evaluation and treatment of women with pelvic floor disorders including urinary and fecal 

incontinence as well as pelvic organ prolapse. We have substantially contributed to the Network 

activities by participating at all levels of clinical trial design, implementation, recruitment, 

intervention implementation, retention and scientific reporting. We have reported outcomes and 

implication for care of these research initiatives at national and international scientific meetings 

and we are committed to continuing these activities. Through this application with its concept 

proposal, we wish to highlight our ability and commitment to continue these meaningful research 

activities. Current common treatment options for fecal incontinence (Fl) include behavioral 

therapy consisting of pelvic muscle exercises, diet and defecatory strategies and surgical 

approaches including anal sphincter repair, artificial bowel sphincter and as a last resort, 

colostomy. A significant proportion of women with Fl, however, do not gain benefit from 

behavioral therapy or sphincter repair yet do not wish to undergo colostomy. As the population 

of post-reproductive women continues to increase, it is imperative to study other treatment 

options that improve quality of life for this condition. An existing modality called sacral 

neuromodulation (SNM, Interstim(R)) has been FDA approved and utilized for the treatment of 

refractory urge incontinence. Two small randomized trials and several cohort studies have shown 
138

efficacy of sacral neuromodulation for the treatment of refractory Fl (although it is not yet FDA 

approved for this indication). We propose a randomized trial to credibly characterize the effect of 

SNM on Fl episodes, symptom specific quality of life, effect on other pelvic floor symptoms, 

sexual function, predictors of response, adverse events, cost effectiveness and the role of 

biomarkers in optimal and suboptimal responses to this treatment. This information will allow us 

to more effectively individualize treatment for women with this condition. 

1-U10-HD-069025-01

RCT of Hypnotherapy vs Tpolterodine for OAB: Voiding and Brain Activation Changes

Rogers, Rebecca

University Of New Mexico Health Science Center 

$25,000

Pelvic floor disorders are common and costly. Performance of rigorously designed, target 

randomized clinical trials that inform evidence-base health care practices for women with pelvic 

floor disorders is best done through collaboration with other clinical sites. The University of 

New Mexico is a highly productive clinical and research site and proposes to join the Pelvic 

Floor Disorders Network in order to meet the Network's goal of investigating innovative 

solutions to these common problems. The University of New Mexico (UNM) proposes to join 

the Pelvic Floor Disorders Network (PFDN) to achieve the Network's primary goal of 

conducting rigorous, multi-center clinical trials to investigate the clinical and health aspects of 

pelvic floor disorders in women. Our site, in collaboration with other Network sites, aims to 

reduce the burden of pelvic floor disorders on women and their families. Through the design of 

innovative trials and participation in ongoing studies, the UNM PFDN site will make significant 

contributions to the Network. Dr. Rogers, Principal Investigator, and Dr. Komesu, Alternate 

Principal Investigator, have extensive experience in the design and conduct of multi-center 

randomized trials and proven leadership and productivity. The UNM PFDN site brings to the 

Network a busy clinical service with large numbers of under- represented Hispanic and Native 

American populations, as well as broad institutional support from the Department of Obstetrics 

and Gynecology and a recently funded Clinical and Translational Research Center. The concept 

proposal, based on preliminary data generated by our site and the work of others, is an innovative 

investigation comparing hypnotherapy to long-acting anticholinergic medicine for the treatment 

of overactive bladder (OAB). In addition to the hypnotherapy comparative-effectiveness trial, the 

concept proposal focuses investigation into the underlying mechanisms of OAB on the brain, 

using functional magnetic resonance imaging (fMRI). This translational, comparative 

effectiveness clinical trial is an excellent example of cutting edge research that the UNM PFDN 

site will bring to the Network. Skilled investigators, a busy clinical practice, unique patient 

populations and broad institutional support make UNM a worthy new clinical site for the PFDN. 

2-U10-HD-041267-12

Pelvic Floor Disorders Network - Duke University Clinical Site

Visco, Anthony G

Duke University

$25,000
139

Female pelvic floor disorders represent a major public health burden given their high prevalence, 

impairment of quality of life, and substantial economic costs. As part of the Pelvic Floor 

Disorders Network, Duke University Medical Center is committed to actively participating in 

innovative clinical trials aimed at improving the evaluation and treatment of pelvic floor 

disorders through high-quality, high-impact clinical research. Pelvic floor disorders research at 

Duke University Medical Center (DUMC) is sophisticated and comprehensive with committed 

investigators addressing issues of great importance to women. DUMC has a tradition of 

excellence in clinical care, training and research in pelvic floor disorders and includes one of the 

nation's first accredited fellowship programs in the field. DUMC offers detailed evaluation and 

treatment in a high-volume, multidisciplinary setting that serves as a tertiary referral center for 

women across the southeast US. Each of the five Duke urogynecology investigators is 

fellowship-trained with expertise in both surgical and non-surgical management of urinary 

incontinence (Ul), pelvic organ prolapse (POP), fecal incontinence, and defecatory dysfunction. 

Last year, our Division cared for more than 1550 new patients and performed more than 400 

surgical procedures for Ul and 270 for POP. Our patient population is 80% Caucasian, 15% 

African American, 2% Asian and 2% Hispanic, from both suburban and rural communities with 

stable care and follow-up patterns. DUMC is the hub of a multidisciplinary team of outstanding 

collaborative investigators in urogynecology, urology, colorectal surgery, gastroenterology, 

maternal-fetal medicine, physical therapy and epidemiology. DUMC offers a wide range of 

diagnostic resources: multi-channel urodynamic testing, video urodynamics, cystoscopy, 

defecography, pelvic MRI, endoanal ultrasound, and needle electromyography. During the 

current PFDN cycle, DUMC-initiated three active RCTs: 1. Anticholinergic vs Botox RCT 

(ABC, Dr. Visco, currently enrolling), Interstim vs Botox RCT (ROSETTA, Dr. Amundsen, full 

protocol), and a RCT evaluating transvaginal mesh for prolapse repair (Dr. Weidner, miniprotocol planned for fall of 2010. DUMC has consistently been a high recruitment site across a 

wide range of non-surgical and surgical studies with unparalleled retention rates. We have 

proven our ability to support and successfully complete large-scale, multi-centered investigations 

through our robust clinical practice and exceptional research infrastructure. Accordingly, Duke 

University Medical Center is well equipped and uniquely qualified to continue as a valuable and 

productive member of the Pelvic Floor Disorders Network. 

1-U10-HD-069006-01

Pittsburgh Pelvic Floor Research Program

Zyczynski, Halina M

Magee-Womens Res Inst And Foundation

$25,000

Though prosthetic mesh enhances durability of prolapse and incontinence repairs, escalating 

complications have prompted public health warnings. Understanding the pathophysiology of 

mesh related morbidity and identifying modifiable risk factors through comparative and 

translational studies will inform on complications, support guidelines on mesh selection and 

route of delivery, and direct innovations in mesh technologies. The purpose of this proposal is to 

demonstrate the capabilities of the University of Pittsburgh to participate as a clinical site in the 

NICHD-sponsored Pelvic Floor Disorders Network (PFDN). Our site has a longstanding track 

record of successful contribution to multicenter studies of urinary and fecal incontinence, and 
140

pelvic organ prolapse. We are particularly well suited to be a clinical site in the PFDN because of 

our volume, research infrastructure and track record, basic and translational experience and 

expertise. Access to large numbers of nulliparous women enables us to contribute uniquely to 

studies of the role of pregnancy and parturition in the etiology and prevention of pelvic floor 

disorders (PFDs). Magee-Womens Hospital (MWH) is the central resource for gynecologic 

specialty care for the 19 hospital University of Pittsburgh Health System serving a very large 

aging population. Our site brings expertise in urogynecology, physical therapy, geriatrics, 

urology, gastroenterology and mental health. We offer unique technical expertise in genomics, 

proteomics, tissue regenerative techniques, biochemical and biomechanical impact of meshes on 

the vagina and central neuronal control of bladder function. We propose to establish a 

comprehensive, scientifically rigorous clinical and translational research program within the 

PFDN for prospective comparative studies of mesh materials used in prolapse and incontinence 

procedures. The program will generate data of immediate clinical relevance as it will present 

scientifically sound, vendor independent evidence to guide surgeons' selection of specific graft 

materials and evidence-based practice guidelines for management of mesh complications. The 3 

major components of the proposal are: 1) mesh specific infrastructure for implementation in 

PFDN clinical trials employing mesh inclusive of the development of a Mesh Morbidity Index 

and establishment of a Biospecimen Repository 2) the first RCT of meshes selected through 

rigorous analyses of biomechanical and biochemical properties and 3) translational studies on the 

cellular response to mesh materials and pathophysiology of mesh complications. The RCT will 

serve to pilot the database, compare clinical outcomes of meshes whilst providing specimens for 

translational studies.

RESPIRATORY DISEASES/CONDITIONS

1-U19-AI-095219-01

Pathophysiologic And Therapeutic Mechanisms Of Aspirin Exacerbated Respiratory 

Disease

Boyce, Joshua

Brigham And Women's Hospital

$12,500

This Proposal for support of an Asthma and Allergic Disease Cooperative Research Center 

(AADCRC) grant is focused on the mechanistic basis of aspirin-exacerbated respiratory disease 

(AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of 

individuals with severe asthma and recurrent nasal polyps. AERD is associated with both 

characteristic clinical reactions to ingestion of nonselective inhibitors of cyclooxygenase (COX), 

persistently elevated generation of the cysteinyl leukotrienes (cys-LTs), especially during 

reactions to aspirin, and selective airway hyperresponsivness to leukotriene E4 (LTE4), the most 

stable and abundant of the cys-LTs. We have discovered a molecular pathway through which 

LTE4 induces pulmonary inflammation (requiring P2Y12 receptors and platelets) and vascular 

leak (requiring a putative novel LTE4 receptor, GPR99). We have also discovered that 

leukocytes from individuals with AERD display a defect in expression of COX-2 and COX-2-
141

dependent generation of prostaglandin E2 (essential to maintain homeostasis in AERD), and that 

this reverses with desensitization to aspirin. We have also found that platelets and leukocytes 

from individuals with AERD lack the EP2 receptor for PGE2. A team of highly accomplished 

investigators with complementary skills will apply cellular, molecular, and whole animal 

strategies, combined with a proof-of-concept clinical trial to determine the cellular and molecular 

basis for these findings, their relevance to disease pathophysiology, and their amenability to 

therapy. Project 1 (J. Boyce, PI) focuses on the physiologic and functional consequences of EP2 

receptor deficiency, and determines its epigenetic basis. Project 2 (Y. Kanaoka, PI) will verify 

the identity and function of GPR99 and determine its susceptibility to desensitization and its 

requirement for downstream effectors (platelets, P2Y12, and thromboxane) to elicit physiologic 

responses. Project 3 (E. Israel, PI) will determine the efficacy of P2Y12 antagonism on the 

severity of clinical reactions to aspirin, and the mechanism by which aspirin treatment restores 

COX-2-dependent PGE2 generation. The coordination of the AADCRC is enhanced by an 

administrative Core.

1-U19-AI-095227-01

Host and Viral Determinants of Infant and Childhood Allergy and Asthma

Peebles, R Stokes

Vanderbilt University Medical Center 

$12,500

The long term objective of this application is to define the relationship between infant respiratory 

syncytial virus (RSV) infection and the host response that enables asthma inception. There is 

abundant evidence that children who experience severe RSV bronchiolitis during infancy are at 

greater risk for developing asthma later in childhood; however the host and viral determinants of 

severity of illness are not fully defined. Also unknown is whether mild RSV-induced illness in 

infancy may protect against the subsequent development of childhood asthma. In Project 1, we 

utilize the ReSPIRA (Respiratory Study for Protection of Infants from RSV to Asthma) cohort of 

2000 infants to focus on host immune responses to RSV infection and the subsequent risk of 

recurrent wheezing and childhood asthma. Specifically, in Project 1 we will a) establish the 

relationship between the host phenotypic response to RSV infection in the first 6 months of life 

and the risk of recurrent wheeze and asthma, and b) identify the host genetic and immune 

response determinants of the RSV infection phenotype that affect the development of early 

childhood wheezing and asthma following RSV infection. In Project 2, we will focus on the 

contribution of specific RSV strains to early childhood wheezing and asthma development. RSV 

strains isolated from the ReSPIRA cohort will be genotyped and clinical parameters such as 

bronchiolitis severity score, as well as mediators of the host immune response measured in 

respiratory secretions will be studied to determine how RSV genotypes impact the host response. 

In Project 3, we will utilize a mouse model of RSV infection to examine the role of the 

prostaglandin 12 (PGI2) on airway dysfunction of an RSV strain (01/2-20) that has been 

associated with severe infant bronchiolitis and which induces airway pathology in the mouse. We 

previously reported that PG12 and signaling through its receptor (IP) is a critical determinant of 

severity of illness in RSV strain A2 infection. This project will determine the role of host PGI2 

in RSV airway pathogenesis and also determine if a PGI2 analog currently used in the treatment 

of human disease is a target for RSV bronchiolitis. Further, in Project 3, we will use RSV strains 
142

isolated from ReSPIRA in Project 2 to determine the generalizability of PGI2 as a therapeutic 

target.

1-U19-AI-095230-01

Airway inflammation and HLA-G in asthma

White, Steven R

University Of Chicago

$12,500

Our program seeks to clarify cellular and molecular mechanisms that lead to chronic asthma in 

order to identify novel, more effective therapies. We concentrate on immune mechanisms that 

underlie chronic airway inflammation with a clear focus on one immune tolerance molecule, the 

class I major histocompatibility complex protein human leukocyte antigen (HLA)-G, that we 

believe has an important role in modulating airway inflammation that is critical to chronic 

asthma. The key premise of our AADCRC proposal is that understanding the role of HLA-G will 

lead to new and better therapies to alleviate the suffering caused by asthma. To this end we

propose three highly integrated and related projects: in Project 1, we will examine the presence 

and regulation of expression of HLA-G in asthmatic airways and in the airway epithelium, and 

relate presence to asthma severity and to the expression of regulating microRNA. We will 

examine the regulation of HLA-G expression by key Th2 cytokines such as IL-13 that are 

important to chronic asthma and relate expression back to airway cytokine concentrations in 

chronic asthma. In Project 2, we will exploit naturally occurring genetic variations in HLA-G 

and its LILRB receptors to understand how signaling through HLA-G and its receptors regulate 

the transition of CD4+ lymphocytes to the Th2 phenotype in mild/moderate asthma and to the 

Th17 phenotype in severe asthma. This project also will examine how genetic variation in the 

LILRB receptors modulate the effects of HLA-G on both T cell phenotype and on the SHP1 and 

SHP2 signaling pathways that modulate airway smooth muscle hypertrophy in chronic asthma. 

In Project 3, we will elucidate mechanisms that account for the higher risk of asthma among 

children of asthmatic mothers compared to children of non-asthmatic mothers. Using HLA-G as 

a model of the interactions of genotype and asthma status in mother and child, we will identify 

differentially expressed genes and the mechanisms for their differential expression in airway 

epithelium, CD4+ T cells and airway smooth muscle in subjects with chronic asthma. To 

complete these projects, each will interact with a robust Patient Recruitment and Data Analysis 

Core that will recruit 100 carefully phenotyped and genotyped asthmatic subjects and additional 

control subjects, and collect blood and airway biological specimens to be used in each project 

through a Lung Biological Specimens Core that will provide analytical and long-term storage. 

We believe that our current levels of productivity and collaboration combined with new, exciting 

and cutting-edge questions in this proposal will allow us to be successful in achieving our overall 

goal - identifying novel therapeutic targets for chronic asthma.

1-U19-AI-095261-01

T Cell Effector And Regulatory Mechanisms In Asthma And Food Allergy

Luster, Andrew D

Massachusetts General Hospital

$12,500
143

The Massachusetts General Hospital/Harvard Medical School AADCRC entitled "T cell effector 

and regulatory mechanisms in asthma and food allergy" seeks to gain a better understanding of 

the role of allergen-specific effector and regulatory T cells in determining the physiological 

response to an allergen at mucosal surfaces. It is becoming increasingly clear that the net 

outcome of an inflammatory response is the balance of allergen-specific effector T cell activity 

and opposing regulatory T cell activity. Antigen-specific effector and regulatory T cell numbers 

and activity are in large measure determined by the outcome of allergen-loaded dendritic cell 

(DC) interactions with antigen-specific T cells. The MGH/Harvard AADCRC will explore the 

balance of effector and regulatory activity in asthma and food allergy and the ability of 

tolerogenic DCs to affect this balance. The Center will focus on two allergic conditions relevant 

to the mission of the NIAID, namely allergic asthma and food allergy, and utilize two clinical 

models [endobronchial segmental allergen challenge (SAC) and oral immunotherapy (OIT)] as a 

foundation for its studies. Project 1 focuses on the role of antigen-specific effector and regulatory 

T cells in determining airways inflammation and airways hyper-reactivity by correlating the 

numbers, phenotype and function of these cells in allergic asthmatics (AA) and allergic 

nonasthmatics (ANA) using innovative imaging techniques; Project 2 focuses on correlating the 

numbers, phenotype and function of these same T cell subsets with clinical outcomes of milk 

allergic patients undergoing milk OIT; and Project 3 focuses on the ability of tolerogenic DC 

therapy to manipulate the balance between these two opposing T cell populations in favor of 

regulatory T cells and tolerance in both asthma and food allergy. The three interrelated projects 

will be supported by Cores that will recruit, enroll and characterize allergic subjects for SAC and 

OIT, provide MHC class II tetramers to specifically identify and study allergen-specific T cells, 

and perform sophisticated transcriptome phenotypic analysis on T cell and DC subsets. The goal 

of this Center is to understand the balance of effector and regulatory allergen-specific T cell 

activity that determines clinical disease in asthma and food allergy and to establish the utility of 

using tolerogenic DCs to manipulate this balance to induce allergen-specific tolerance. This 

would pave the way for new therapeutic approaches to treat these and other allergic diseases.

2-U19-AI-070235-06

Epithelial Genes in Allergic Inflammation

Khurana Hershey, Gurjit K

Cincinnati Children's Hosp Medical Center 

$12,500

Allergic disorders are a major global health concern affecting 150 million people worldwide. 

Recently, epithelial cells have emerged as central participants in the pathogenesis of allergic 

inflammation: (1) they interface with the environment and initiate the response to environmental 

triggers; (2) the mucosal epithelium in the lung, skin, and gut functions as a physical barrier 

against pathogens and environmental exposures including allergens; and (3) epithelial cells have 

been directly implicated in Th2 responses, serving as a critical interface between innate immune 

responses and Th2 immunity. The overall objective of these studies is to elucidate the 

mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The 

overarching hypothesis of this Center proposal is that epithelial cell genes play a central role in 

the pathogenesis of allergic disorders. This hypothesis will be tested by three integrated projects 
144

that use the Center for coordination and synergistic extension of the projects beyond the scopes 

and capabilities of the individual projects. This Center will provide important insights into the 

genes and pathways that may be Important in epithelial driven allergic inflammation and provide 

a basis for the design of novel therapeutic strategies aimed at the epithelial surface, i.e. lung 

(asthma), skin (atopic dermatitis), or gut (food allergy or eosinophilic esophagitis). Furthermore,

integration of data across projects will provide novel insights into a key question in allergy -

What are the mechanisms underlying tissue specific disease manifestations of allergic 

inflammation? Each project in the Center is focused on distinct epithelial cell genes and their 

roles in allergic disorders. Project 1 will examine the association of epithelial genes with allergic 

diseases that target distinct mucosal surfaces. Project 2 will dissect the role of epithelial 

desmoglein-1 in the pathogenesis of the allergic disorder eosinophilic esophagitis. Project 3 will 

focus on delineating the mechanisms by which epithelial-derived IL-33 is regulated by trefoil 

factor 2 (TFF2) during the early innate immune events that initiate allergy and asthma; and better 

define the role of the TFF2/IL-33 pathway in the pathogenesis of allergic disorders.

2-U19-AI-070412-06

Role Of Unique ADP-Ribosylating Vacuolating Mycoplasma Pneumoniae Toxin In Asthma

Baseman, Joel B

University Of Texas Hlth Science Center

$12,500

The San Antonio Asthma and Allergic Diseases Cooperative Research Center (SA-AADCRC) 

represents a tightly focused, integrative and innovative effort to understand the role of 

Mycoplasma pneumoniae and its unique ADP-ribosylating and vacuolating toxin, designated 

Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX) as important 

mediators of acute and chronic airway diseases, including new onset asthma and exacerbations, 

as well as persistent pulmonary dysfunction in children and adults. The basic science and clinical 

investigators who comprise the SA-AADCRC team share broad expertise and are highly 

collaborative. The SA-AADCRC's broad strategy of attack interlinks basic science and clinical 

research projects and cores. Project 1 uses the murine model and human materials to address 

fundamental questions on how CARDS TX induces asthma-like disease and exacerbates allergic 

pulmonary inflammation. Project 2 focuses on identifying CARDS TX ADP-ribosylating airway 

protein targets, delineating functionally important CARDS TX domains and essential amino 

acids that mediate CARDS TX binding to human surfactant protein A (SP-A) and airway cells, 

and generating antibody reagents that block/neutralize CARDS TX. Project 3 applies state-ofthe-art biophysical techniques to uncover the structure and action of CARDS TX by using single 

crystal X-ray diffraction to determine CARDS TX three dimensional structure in the presence 

and absence of its cofactor NAD; neutralizing monoclonal antibody Fab fragments; and 

surfactant protein-A (SP-A). Clinical Core will collect human material from subjects with well 

controlled asthma, poorly controlled asthma and healthy controls and help in evaluation and 

follow-up of patient-related studies. Diagnostic Core will process clinical and experimental 

samples for diagnostic analysis by providing highly sensitive and specific diagnostic assays for 

rapid detection of M. pneumoniae CARDS TX. Pathology Core will provide necessary biopsy 

and necropsy procedures, lung pathology interpretation, histochemical and immunocytochemical 

evaluations, and qualitative and semiquantitative histopathologicai analyses. Administrative Core 
145

will oversee all SA-AADCRC-related activities and coordinate interactions and collaborations 

between projects and cores. Therefore, the SA-AADCRC represents a network of 

collaborators/colleagues who continuously ask fundamental and translational questions about 

asthma, airway-related pathologies, immunopathogenesis, and M. pneumoniae/CARDS TX 

biology and virulence mechanisms.

2-U19-AI-070489-06

Epithelial Barrier Programs in Asthma and Allergic Disease

Holtzman, Michael J

Washington University

$12,500

The overall goal of this AADCRC proposal is to define the role of the epithelial cell barrier in 

the pathogenesis of asthma and allergic disease and to use that information to prevent this type of 

disease. We combine expertise in airway as well as gut and skin epithelial cell biology, and we 

use cell and mouse models with high fidelity to directly translate our findings to humans. The 

AADRC therefore consists of three interrelated Projects that ask, first, how airway epithelial 

cells mediate effective antiviral defense under one condition but asthma under another (Project 

1), second, how airway epithelial cells remodel towards an overabundance of mucous cells in 

post-viral and allergic asthma (Project 2), and third, how epithelial injury in the skin triggers the 

march from atopic dermatitis to asthma (Project 3). Each project addresses the respective 

question with a novel but overlapping molecular approach to mechanism and takes advantage of 

a breakthrough discovery to set a new scientific paradigm for the system under study. Thus, 

Project 1 unravels a new IFN signaling pathway that offers improved protection against viral 

infection and post-viral asthma and is specific to the airway epithelial cell barrier; Project 2 

dissects a new pathway for autophagy proteins to support proper mucous cell function and 

prevent mucous cell metaplasia in the airway in a manner reminiscent of the intestinal epithelial 

barrier; and Project 3 defines a new TSLP production and secretion pathway that drives airway 

inflammation based on its expression in the skin epithelial barrier. Each Project is constructed so 

that the first aim will establish a basic pathogenic mechanism using cell and mouse models that 

are shared among projects and supported by the Cores for tissue and cell processing (Core C) and 

mouse models (Core D). In turn, each Project will conduct a second aim to validate and translate 

its findings using samples from children and adults with asthma and/or atopic dermatitis supplied 

by the Core for human subjects and data analysis (Core B). Sharing samples and overlapping 

scientific goals among projects create a synergistic program that can be coordinated by a 

common Administrative Core (Core A). Project and Core interactions are based on the overall 

principle that each Project begins with molecular hypothesis building in cell and mouse models 

and translates findings from these models to studies of humans with asthma and/or allergy. In 

each project, we aim to validate a clinically useful biomarker of the disease process and lay the 

groundwork for the future development of biological and/or small molecular weight compounds 

that might influence the process as a therapeutic strategy.

2-U19-AI-070535-06

Airway Inflammation And Airway Remodeling

Broide, David H
146

University Of California, San Diego

$12,500

Airway remodeling is the term applied to the structural changes observed in the airway in 

asthma. Although current NIH guidelines recommend maintaining a goal of normal lung 

function in asthma, current therapeutic strategies do not specifically target airway remodeling as 

the cellular and molecular mechanisms that result in remodeling are not well defined and thus 

therapeutic targets are not well understood. Thus, there is an important need to identify 

mechanisms by which airway remodeling is mediated so that potential novel therapies could be 

directed at these pathways. In addition, characterization of these pathways could lead to the 

development of non-invasive blood or sputum biomarkers to identify, monitor, and perhaps 

subset, patients with asthma and remodeled airways. This UCSD AADCRC proposal will be 

directed by David Broide (Professor of Medicine) and include three projects (Broide, Croft, 

Zuraw) that will investigate mechanisms of airway remodeling in asthmatics exposed to allergen 

and rhinovirus common triggers of asthma. Thus, the overall hypothesis that will be explored in 

all three projects is that exposure to allergen triggers expression of inflammatory and remodeling 

pathways in allergic asthmatics that are exacerbated by exposure to respiratory viruses such as 

rhinovirus. The specific hypothesis that will be explored in each project and that will be driven 

by samples from asthmatics, is that the innate immune response (airway epithelium, 

macrophages, natural helper cells) play an important role in initiating and perpetuating the 

inflammatory and airway remodeling response to environmental triggers in allergic asthmatics. 

The three interrelated projects will focus on "Innate inflammation and airway remodeling" 

(Broide, Project 1), "TNF-R family members, inflammation and remodeling" (Croft, Project 2), 

and "Epithelial GILZ inflammation and remodeling" (Zuraw, Project 3) and be supported by 

Administrative Core A, and "Asthma Clinical Core B" which will be a source of sputum, BAL, 

endobronchial biopsy, and blood samples from asthma and control subjects provided by 

investigators in Core B (Ramsdell, Harrell, and Thistlethwaite, UCSD; Proud and Leigh, 

University of Calgary; and Hamid, McGill University). An lOFM Core is also proposed as 

requested by the RFA.

1-R21-HL-109935-01

Uterine-Specific Genetic Modification And Lymphangioleiomyomatosis

Teixeira, Jose M

Massachusetts General Hospital

$50,000

One of the major unknowns in lymphangioleiomyomatosis (LAM) research is the cell or tissue 

of origin for the smooth muscle cells that infiltrate the lung to form the fibrotic lesions. We have 

generated mice with defective wound healing in uteri, which results in hemorrhaging, 

hypertrophic scarring and fibroids. Our preliminary results investigating the lungs suggest that 

circulating post-traumatic uterine cells might be the cells that cause LAM. The proposed studies 

will investigate whether the uterine cells are the source of fibrotic cells found in LAM, whether 

the LAM lung lesions are hormonally responsive, and whether these mutant mice will be a 

needed model system for investing the mechanisms and pathways involved in the infiltration of 

the lungs with fibrotic cells and for preclinical studies of possible therapeutic intervention. 
147

Lymphangioleiomyomatosis (LAM) is a rare disease primarily found in females and is 

characterized by a diffuse interstitial infiltrate of atypical smooth muscle cell lesions in the lung 

parenchyma resulting in airway restriction. The etiology of the disease is unknown but is thought 

to involve hormonal regulation because it usually presents between menarche and menopause. 

Additionally, LAM is often found in patients with mutations in tuberous sclerosis complex 

(TSC), suggesting that inactivation of TSC can contribute to its development. We are studying 

uterine development and associated pathologies by conditionally deleting and/or activating 

candidate genes in pathways critical for normal differentiation and function. We have created 

mice with uterine-specific leiomyomas (fibroids) by either constitutively activating ¿-catenin or 

by expressing a truncated allele of adenomatous polyposis coli (APC) and we have shown 

preliminary evidence that the leiomyomas develop as a result of vascular hemorrhaging and 

subsequent hypertrophic scarring. The Mullerian duct-derived internal female reproductive tract 

organs (uterus, oviduct, cervix, and cranial portion of the vagina) are the only structures from the 

bipotential mammalian embryo not found in males, suggesting that the hormonally responsive 

mesenchymal stromal cells of the uterus might be the source of the cells for pulmonary fibrosis 

and account for the female-specificity of LAM. We hypothesized that pulmonary LAM might be 

caused by uterine vascular pathologies that allow intravasation of uterine stromal cells that can 

subsequently lodge and proliferate in the lungs. Histological analysis of the lungs from our 

mouse models with uterine hemorrhaging and leiomyomas showed fibrotic lung plaques similar 

to that observed in human LAM that were also HMB45-, aSMA- and desmin-positive, markers 

for human LAM. We propose to investigate this hypothesis further with the following Specific 

Aims: (1) confirm that cells in the lung lesions are derived from the uterus, (2) determine 

whether uterine mesenchymal cells can be detected in peripheral blood, (3) test the hormone 

responsiveness of the smooth muscle cells in the lung lesions, and (4) assess the marker profile 

of lung lesions for comparison with human LAM. The results from these studies will lay the 

foundation for continued investigation of the triggers and signaling pathways involved in the 

development of the LAM lesions as well as provide an in vivo model system for preclinical 

studies of therapeutics targeting those pathways. 

OD-11-289

Workshop On The Health Impacts Of Indoor Air Pollution In Developing Countries

Martin, William

NICHD

$7,854

An international workshop was convened May 9-11, 2011 in Arlington, VA to discuss current 

evidence on adverse health effects of indoor air pollution and to exchange views on improving 

human health. Every day, millions of women in developing countries spend several hours 

crouched over small fires cooking. Often their homes have no chimneys and poor ventilation. 

This daily proximity destroys lungs and small children staying close to their mothers are equally 

vulnerable. Exposure to smoke from traditional stoves and open fires – the primary means of 

cooking and heating for 3 billion people in developing countries – causes almost 2 million deaths 

annually, with women and young children affected most. The World Health Organization states 

that indoor air pollution in developing countries is the fourth leading cause of morbidity and 

mortality, and the second leading environmental contributor to ill health affecting primarily 
148

women and children. New designs in cooking stoves are not always comfortable for the women 

cooking on them, and require changes in cooking methods, some of which made the food taste 

different. In the kind of patriarchal societies that keep women tied to stoves and kitchen 

responsibilities, women don’t have a lot of autonomy for decision-making, especially not about 

major household issues like a new stove. At this workshop, more than 150 scientists and policy 

makers from multiple countries focused on research gaps, exposure assessment, and the 

burgeoning global initiative that aims to deliver clean, affordable cook stoves to the developing 

world. The workshop presented a first-ever opportunity to hear the state-of-the-science on the 

health impacts of indoor air pollution and to identify critical research needs. The need for such a 

meeting is considerable since the poorer half of the world’s population uses biomass — wood, 

crop residue, or dung — or coal as fuel to cook and heat, contributing to a variety of health 

conditions including pneumonia, lung cancer, cardiovascular disease, low birth weight, and 

cognitive impairment. Speakers described the importance of biomarkers and the development of 

inexpensive, portable electronic monitors as a means to gather exposure assessment data. 

RESEARCH DISSEMINATION

NLM-ORWH Women’s Health Web Portal and Research Dissemination

A Partnership between NLM and ORWH

$550,000

The funding for research dissemination projects for the NLM-ORWH Women’s Health 

Resources Web Portal http://www.womenshealthresources.nlm.nih.gov is being distributed 

throughout the United States to fund meritorious and innovative outreach programs that use 

Women’s Health Resources as an information dissemination tool to consumer and professional 

audiences. Projects will target consumers, professionals, both groups, or women overseeing and 

coordinating health of their families. Types of projects include development of campaigns, 

trainings, toolkits or other activities that can be replicated. These projects will enhance the

dissemination of the key elements identified in the ORWH strategic plan, Moving Into the Future 

With New Dimensions and Strategies: A Vision for 2020 for Women’s Health Research that was 

released in September 2010. Projects will provide an outcomes summary and evaluation that 

will be posted to the NLM-ORWH Web Portal. There are two levels of funding for the outreach 

award; a maximum of $20,000 for each health professional outreach project, or $15,000 for each 

consumer outreach project. Majority of the awards will be selected from EnHIP member 

universities and colleges and the National Network of Libraries of Medicine members. 

Descriptions of each group follows. 

The National Library of Medicine’s Environmental Health Information Partnership (EnHIP)

is a collaboration between the Library and twenty-one Historically Black Colleges and 

Universities (HBCUs), Hispanic-Serving Institutions (HSIs), Tribal Colleges and Universities, 

and Alaska Native-Serving Institutions to address health disparities. EnHIP evolved from the 

Toxicology Information Outreach Program (TIOP) that was established in 1991 in response to 

the pressing issue of toxic waste and the exposure to toxic chemicals in minority communities. 
149

The mission of EnHIP is to enhance the capacity of minority serving academic institutions to 

reduce health disparities through the access, use and delivery of environmental health 

information on their campuses and in their communities. More information, a list of current and 

former member schools and reports of past efforts can be found at: 

http://sis.nlm.nih.gov/outreach/enhip.html . 

The National Network of Libraries of Medicine (NN/LM) has been serving the biomedical 

information needs of the nation for over forty years by providing health professionals and the 

general public with health information resources and services. The mission of NN/LM is to 

advance the progress of medicine and improve the public health by providing all U.S. health 

professionals with equal access to biomedical information and improving the public's access to 

information to enable them to make informed decisions about their health. The Program is 

coordinated by the National Library of Medicine and carried out through a nationwide network 

of health science libraries and information centers. The NN/LM equips and encourages Network 

members to extend their services and expertise to groups, agencies, and institutions beyond their 

traditional reach into communities also targeting consumers and those that serve consumers. 

More information about the NN/LM can be found at: http://nnlm.gov/ .