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Office of Research on Women's Health (ORWH)

Research Summaries, FY 2010*

Office of the Director

National Institutes of Health

September 2010 
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Table of Contents

ADOLESCENT HEALTH ...............................................................................................................................3

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

ALCOHOL AND OTHER SUBSTANCE ABUSE...............................................................................................5

CANCER .....................................................................................................................................................7

CHRONIC FATIGUE SYNDROME ..............................................................................................................25

CARDIOVASCULAR DISEASE ....................................................................................................................26

CRANIOFACIAL ........................................................................................................................................29

DIABETES.................................................................................................................................................30

DIETARY SUPPLEMENTS/CAM.................................................................................................................33

GENITOURINARY .....................................................................................................................................34

HIV...........................................................................................................................................................36

IMMUNITY/AUTOIMMUNITY..................................................................................................................49

MENOPAUSE ...........................................................................................................................................55

MENTAL HEALTH.....................................................................................................................................63

MUSCULOSKELETAL SYSTEMS.................................................................................................................66

NEUROLOGY/NEUROSCIENCES...............................................................................................................71

NUTRITION..............................................................................................................................................74

OBESITY/OVERWEIGHT...........................................................................................................................75

PAIN ........................................................................................................................................................76

REPRODUCTIVE HEALTH/DEVELOPMENTAL BIOLOGY............................................................................80
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ORWH RESEARCH SUMMARIES, FY 2010

ADOLESCENT HEALTH

5P01 HD031921-15

The National Longitudinal Study of Adolescent Health (Add Health)

Harris, Kathleen M

University of North Carolina, Chapel Hill

$200,000

Add Health is currently funded for Wave IV data collection. At the time the project began in 

1994-1995, investigators selected a nationally representative sample of adolescents in grades 

seven through 12. Participants have been followed through adolescence and the transition to 

adulthood with three in-home interviews. Wave IV will include additional information that 

encompasses social, behavioral, and biological data. In addition to data contributed in earlier 

surveys, these subjects, who are now between the ages of 23 and 31 years, will provide 

biological data to capture the prevailing health concerns as well as biological markers of future 

chronic health conditions. 

1 R34 MH086922-01A2

An Integrative Intervention for Binge Eating Among Adolescent Girls

Mazzeo, Suzanne, Ph.D.

Virginia Commonwealth University, Richmond, VA

$200,000

Many adolescents struggle with overeating (binge-eating). Adolescents with these eating 

problems are more likely than their peers to be depressed, anxious, and feel badly about their 

appearance. African American girls are especially at-risk for these eating problems. Effective 

treatments are urgently needed. This study will develop and evaluate an innovative intervention 

(LIBER8-Linking Individuals Being Emotionally Real) for ethnically diverse adolescent girls. 

This intervention will focus on teaching girls skills that help them reduce their problematic 

eating behaviors and improve their overall well-being. Binge and loss of control (LOC) eating 

affect a significant number of adolescents of all ethnicities and are associated with numerous 

psychological problems, including depression, anxiety, low self-esteem, body dissatisfaction, and 

weight concerns. African American women appear to be particularly vulnerable to binge eating 

disorder, and LOC and binge eating are prevalent among African American girls. However, 

empirically validated culturally sensitive treatments for these disordered eating behaviors are not 

available. Thus, this R34 application aims to develop a manualized and culturally sensitive 

intervention (LIBER8-Linking Individuals Being Emotionally Real) for African American and 

White adolescent girls targeting binge and LOC eating. They will target the intervention to 

adolescents with either or both behaviors. This intervention will integrate components of 

dialectical behavior therapy tailored to adolescents who engage in binge and LOC eating, such as 

mindfulness and distress tolerance skills training, with a core of cognitive-behavioral therapy 

(CBT). They will seamlessly integrate a key adolescent communication strategy, namely textmessaging, into therapeutic self-monitoring. They will evaluate the feasibility and acceptability 

of the intervention in a controlled pilot trial. This study is designed explicitly to gather 
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preliminary data to inform a subsequent larger randomized controlled trial. They hypothesize 

that this intervention will serve to reduce binge and LOC eating, as well as improve psychosocial 

functioning as evidenced by decreased depression, anxiety, eating disorder cognitions, and 

impulsivity, and improved quality of life. 

NHANES Project For Adolescents And Girls

Troiano, Rick

NCI, Bethesda, MD

$300,000

NHANES data from 2003-2006 show a dramatic decline in physical activity, especially for girls, 

as children move into adolescence. Poor sleep and loss of muscle strength are an issues for 

women as they age. The NHANES will measure physical activity, sleep and muscle strength for 

women and men across the life span from a nationally representative sample.

AGING

5 R37 AG030481-03

National Social Life, Health, and Aging Project

Waite, Linda J.

National Opinion Research Center, Chicago, IL

$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 
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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. 

ALCOHOL AND OTHER SUBSTANCE ABUSE

5 R21 DA027145-02

An Ethnographic and Economic Investigation of the Fresh Start Program (Detroit)

Roddy, Juliette Kathryn

University of Michigan. Dearborn, MI

$154,500

Treatment professionals and substance abuse researchers agree that both successful drug abuse 

recovery and exiting street prostitution require changes in social networks and accompanying 

economic independence. These changes can be both quantitatively and qualitatively described by 

studying street prostitutes who are engaged in the treatment and recovery process through the 

application of ethnographic and economic instruments and an accompanying mapping of 

changing social networks. The proposed work has implications for women's health and welfare 

and the prevention and treatment of sexually transmitted disease. Aside from journalistic 

accounts detailing the pitfalls of drug treatment, little research has been done on the recovery 

process as it actually proceeds within particular programs. Research is not always well 

incorporated into treatment settings, which may resist innovations due to internal organizational 

factors. Conducting research in criminal justice settings, including drug courts or programs 

administered through drug courts, is also problematic. Nonetheless, more such research is needed 

as treatment and recovery services become central features of the national response to substance 

abuse, especially in an era of prison downsizing. This will also require research that actively 

engages with communities and institutions. The proposed research will work collaboratively with 

multiple agencies to investigate the process of treatment and recovery as it occurs in women who 

participate in Fresh Start. Fresh Start is a substance abuse intervention program for female street 

sex workers who have come into repeated contact with law enforcement. Fresh Start is a coercive 

recovery-based program that serves as a direct contrast to voluntary, traditional, treatment-based 

programs. The program serves as an alternative to jail time for these women, who are arrested in 

periodic sweeps of neighborhoods where street prostitution is common. They predict that, prior 

to entering residential treatment through Fresh Start, women will have daily routines dominated 

by "street" networks that are relatively constricted and immersed in drug use and drug- using 

contexts. For those that enter residential treatment and stay in the program for a year, they

predict that networks will remain relatively constricted, but will instead be largely immersed in 

treatment-dominated contexts. In the recovery stage, women will be engaging with the larger 

community, that is, interacting with more people who are not in treatment or recovery. In this 

stage, they predict that networks may grow more extensive and variable, as women begin to 

explore new avenues of social interaction and opportunity. Using interdisciplinary methods, they
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will seek evidence of desired change in social networks, sociospatial contexts, and economic 

behaviors, resources and outcomes. 

5 R21 AA018398-02

Interactive Effects Of Ethanol And Estrogen On Brain Vasopressin During Puberty

Pak, Toni R.

Loyola University Chicago

$186,875

Women who abuse alcohol are twice as likely to develop anxiety disorders compared with men, 

a phenomenon in which the underlying biological mechanisms are unknown. This proposal is 

focused on a specific candidate gene (AVP) and its downstream signaling pathways that are 

developmentally shaped during puberty. They expect these studies to show that AVP is 

permanently altered, either as a direct target for alcohol or indirectly through steroid hormone 

receptor signaling pathways. Thus, the value of this research lies in the potential for therapeutic 

approaches that would target specific genes and perhaps reverse brain damage caused by alcohol 

consumption during pubertal development as well as strengthen reasons for abstaining from 

alcohol during that time. Women who abuse alcohol are twice as likely to develop anxiety 

disorders compared with men, a phenomenon in which the underlying biological mechanisms are 

unknown. Their overall objective is to identify the interactive effects of alcohol and estrogen on 

arginine vasopressin (AVP), a well-established key molecular mediator of anxiety, in order to 

elucidate the molecular mechanisms predisposing women to increased risk of anxiety disorders. 

Adolescent binge drinking is a potential risk factor for the development of adult anxiety 

disorders due to the heightened stress reactivity that occurs as a direct result of increased 

circulating estrogens during pubertal development. Little is known about the long-term 

neurobiological consequences of alcohol consumption during puberty, which is a dynamic and 

important period of brain development that involves changes in cortical gray matter, synaptic 

connectivity, and increased neurogenesis. Exposure of alcohol during this critical period of 

extensive brain remodeling may result in permanent neuronal damage or disruptions in the 

formation of new neuronal connections, which might manifest as adult behavioral psychoses, 

including anxiety disorder. Their preliminary data show that 1) alcohol exposure during puberty 

increased AVP gene expression in specific regions of the brain. Therefore, the experiments 

proposed in Specific Aim 1 will directly test the hypotheses that there is a critical window of 

time during pubertal development when the AVP system is most vulnerable to the effects of 

alcohol and (2) that estrogen exacerbates the effects of alcohol on AVP gene expression. Also, 

their preliminary data demonstrate that alcohol treatment and estrogen receptor ligands increased 

AVP gene expression in neuronal cells derived from the hypothalamus, and gene expression is 

closely correlated with the activity of the gene promoter. Alcohol also activates estrogensignaling pathways in the brain, which suggests that the underlying mechanisms for alcoholinduced changes in AVP may be mediated by estrogen signaling pathways. Therefore, the 

experiments proposed in Specific Aim 2 will directly test the hypotheses that (1) acute alcohol 

exposure increases AVP promoter activity in neuronal cells, (2) that there are specific regulatory 

regions of the AVP promoter that interact with alcohol, and (3) that estrogen and alcohol interact 

synergistically to increase AVP promoter activity. To date, specific molecular and 

neuroendocrine markers that are activated by alcohol during puberty have not been identified. 

This proposal is focused on a specific candidate gene (AVP) and its downstream signaling 

pathways that are developmentally shaped during puberty. They expect these studies to show that 
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AVP is permanently altered, either as a direct target for alcohol or indirectly through steroid 

hormone receptor signaling pathways. Thus, the value of this research lies in the potential for 

therapeutic approaches that would target specific genes and perhaps reverse brain damage caused 

by alcohol consumption during pubertal development as well as strengthen reasons for abstaining 

from alcohol during that time.

CANCER

1 R21 CA149803-01A1

A Decision Making Framework for Contralateral Prophylactic Mastectomy

Brewster, Abenaa, M.D.

University of Texas MD Anderson Cancer Center, Houston, TX

$191,327

The rising incidence of contralateral prophylactic mastectomy (CPM) among patients with 

sporadic breast cancer for whom there is no established psychosocial or clinical benefit or cost 

data is a critical area of public health concern. The proposed study will evaluate the clinical 

benefits, risks and cost of CPM and prospectively evaluate the decision making process leading 

to CPM among women with sporadic breast cancer. The results of the study will be used to 

develop a clinical educational instrument that will enable patients with sporadic breast cancer 

and their providers to make more informed decisions regarding CPM which will serve to 

improve the quality of life of breast cancer survivors. The two specific aims are: 1a) Assess the 

association between CPM and disease-free survival (defined as contralateral breast cancer, 

distant recurrence and breast cancer mortality), 1b) Assess the health care resource utilization 

associated with CPM, which will include the surgical procedure, management of surgical 

complications and subsequent breast reconstruction and 2) Prospectively examine the 

psychosocial characteristics and decision-making process of women considering CPM. The 

hypothesis is that CPM will marginally improve disease-free survival, add substantial costs to the 

health care system and that patients with more cancer-related distress will be more likely to 

consider CPM. The findings from this study will form the basis for future research (e.g., 

intervention and/or observational studies) in this area that may be expanded to include multiple 

institutions. The proposed study is innovative because there are no studies to date that have 

prospectively evaluated the psychosocial factors that contribute to the decision-making process 

leading to CPM among patients with sporadic breast cancer. This research is important because 

of the rising incidence of CPM and the exposure of an increasing number of women to 

aggressive surgical management without established psychosocial or clinical benefit. The longterm impact of the proposed research is significant because it will lead to the development of an 

evidence-based clinical educational intervention that will enable patients with sporadic breast 

cancer and their providers to make more informed decisions regarding CPM and improve the 

quality of life of breast cancer survivors.

1 R03 CA141572-01A1

Can Lifestyle Modify Fatigue in Breast Cancer Survivors?

Chen, Wendy Y.

The Brigham and Women's Hospital, Inc

Boston, MA
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$89,000

With over 2 million breast cancer survivors in the United States, the investigators propose to 

evaluate the determinants of fatigue with a specific focus on new-onset and persistent fatigue 

among breast cancer survivors and an innovative exploration of dietary modifiers of fatigue. 

Fatigue is the most common and distressing symptom among breast cancer survivors and can 

persist for years after treatment, even in those clinically disease-free. Most studies among cancer 

survivors have evaluated the prevalence of fatigue using a cross-sectional design with limited 

longitudinal follow-up and none of the published studies to date have data on subjects before 

diagnosis. They propose to utilize the prospective Nurses' Health Study (NHS) cohort, which

includes data on subjects before and after cancer diagnosis as well as a cancer-free comparison 

group, to evaluate the prevalence and trajectory of fatigue among breast cancer survivors not 

currently on treatment and the influence of lifestyle factors affecting the inflammatory pathway, 

a possible causative mechanism. They will examine both persistent (present before and after 

diagnosis) and new-onset fatigue (lack of fatigue before diagnosis and development of fatigue 

after diagnosis). Strengths of the NHS dataset include data collected prospectively before and 

after diagnosis, availability of a comparable control group, and extensive information on dietary 

and lifestyle factors before and after diagnosis with an excellent follow-up rate. Although the 

cause of fatigue among cancer survivors is most likely multi-factorial, increasing evidence 

suggests that inflammation is an important mediator. Breast cancer survivors with fatigue have 

higher levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factoralpha (TNF-1), and circulating T lymphocytes compared with survivors without fatigue. In 

addition, dietary intake can modify inflammatory biomarkers relating to cardiovascular disease 

and the metabolic syndrome. Therefore, if inflammation is a mediator of fatigue, lifestyle factors 

that modify inflammatory pathways may also influence fatigue among survivors. Using data both 

before and after cancer diagnosis for survivors and cancer-free comparisons, they propose 

analyses to characterize risk factors for persistent and new-onset fatigue among breast cancer 

survivors and lifestyle factors that may modify the development and persistence of fatigue. Their 

findings could lead to new methods of coping with a debilitating symptom and identifying 

women who might best respond to interventions to decrease fatigue. Their application is novel in 

examining dietary modifiers of fatigue. Specifically, they hypothesize that among breast cancer 

survivors that the prevalence of persistent fatigue is similar to that in matched controls without 

cancer, but that new-onset fatigue is more common among breast cancer survivors. They hope to 

identify predictors of new-onset, but not persistent, fatigue, such as age at diagnosis, 

employment status, and lack of physical activity and overweight at diagnosis. Finally, they will 

evaluate dietary modifiers of fatigue including a higher intake of cereal fiber, whole grains, and 

n-3 fatty acids and lower intake of saturated and trans-fatty acids.

1 R21 CA152839-01

Microbial Exposures across the Lifespan and Cancer Risk in Women

Clarke, Christina

Cancer Prevention Institute of California, Fremont, CA

$220,500

Exposure in early life to harmless microbes, as occurs through contact with children, pets, and 

farming environments, could prevent certain cancers in later life through a calibrating effect on 

the immune system. This study, based in a large cohort of California women, will examine 

whether age-specific markers of microbial exposures are associated with the risk of developing 
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malignancies that together account for a large proportion of the cancer burden in US women, 

including cancers of the breast, endometrium, colon, thyroid, and melanocyte. If this study finds 

that these microbial exposures do reduce cancer risk, their results could justify the investigation 

of new cancer prevention strategies using harmless surrogates of important microbial exposures. 

Early-life exposure to harmless microbes, as occurs through exposure to children, pets, and farm 

animals, is increasingly understood to affect childhood health, and mounting evidence suggests 

that these exposures also influence health in adulthood. The likely pathway for this influence 

involves a calibrating effect of early-life microbial exposures on the immune response so as to 

reduce the likelihood of chronic inflammation in later life. As chronic inflammation is known to 

interact with hormone levels and is suspected in the cause of several cancers in women, 

including breast, endometrial, and colon cancers, microbial exposures represent important targets 

of cancer prevention studies. They have preliminary evidence that early-life exposure to farming 

and preschool or kindergarten protects against breast cancer risk later in life, justifying more 

detailed study of these exposures for breast and other cancers, including how the risk 

associations might vary with age-specific exposures across the lifespan. They have a unique 

opportunity to examine relationships between microbial exposures and cancer risk in over 60,000 

women participating in the California Teachers Study (CTS), a cohort of female California 

teachers and administrators followed prospectively for cancer incidence since 1995. Their study 

aims to measure associations between selected markers of microbial burden at a range of ages 

and risk of several cancer outcomes, including in situ breast cancer, estrogen receptor (ER)-

positive and ER-negative invasive breast cancer, type 1 endometrial cancer, cutaneous 

melanoma, colon cancer, and, to the extent possible, papillary thyroid cancer. To accomplish 

these aims, they will conduct a secondary data analysis in the CTS, using a nested case-control 

design, using exposure data collected from 60,878 cohort members who provided information 

about five markers for microbial exposure, including characteristics of their home environment 

at ages 6 months, 3 years, 5 years, 12 years, and 30 years. They will use unconditional logistic 

regression to measure associations adjusted for confounders such as age and socioeconomic 

status. This unified approach will enable us to compare and contrast in a single cohort the 

associations of early- and later- life markers of microbial exposures with risk of hormonedependent cancers (e.g., ER-positive breast, endometrial, and papillary thyroid cancers), 

hormone-independent cancers (e.g., melanoma and ER-negative breast cancer), and cancers 

linked strongly to chronic inflammation (e.g., breast and colon cancers). If they find that these 

understudied environmental exposures do reduce risk of specific cancers or groups of cancers, 

their results could justify the investigation of new cancer prevention strategies using harmless 

surrogates of important microbial exposures. 

N01 CP11005

Costa Rica HPV-16/18 Vaccine Trial (CVT)

Hildesheim, Allan

NCI, Bethesda, MD

$550,000

The ORWH has supported infrastructure costs associated with the Costa Rica HPV Vaccine Trial 

(CVT) since its inception. In FY09, support in the amount of $400,000 was provided. These 

funds were utilized to support continued follow-up and clinical management of the 7,466 women 

enrolled in this community-based, randomized, phase III clinical trial and for the enrollment of 

participants into the extended follow-up phase of the trial (planned for an additional 6 years 
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beyond the initial, 4-year blinded phase). More specifically, funds provided by ORWH in FY09 

supported the following activities: 1) Continued blinded follow-up screening of trial 

participants, 2) Referral of participants with evidence of high-grade disease to colposcopy and 

treatment, 3) Initiation of 4-year study visits (final visit under the blinded design -

Approximately 2,000 such visits of expected total of 7,000 were performed in FY09), 4) 

Consenting of women into their Long-Term Follow-up Study (Approximately 2,000 women of 

expected total of 7,000) were consented in FY09, 5) Initiation of recruitment of new control 

group for the Long-Term Follow-up- Study (Approximately 700 women of expected total of 

3,000) were recruited in FY09, and 6) Additional collection of specimens from the vulva, anus, 

and oral cavity to allow for the evaluation of vaccine efficacy at sites other than the cervix. The 

activities funded by ORWH in FY09 and preceding years have resulted in several important 

publications in the peer-reviewed literature.

1 R03 CA141318-01A1

Nuclear Pore Complex Architecture and Drug Resistance in Ovarian Carcinomas

Kohtz, Donald Stave

Mount Sinai School of Medicine of NYU, New York, NY

$84,750

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. 
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1 R21 CA135570-01A2

Estrogen and Skin Cancer

Oberyszyn, Tatiana

Ohio State University, Columbus, OH

$228,750

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. Their 

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. Their 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 

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

1R21 CA152433-01

Family Cancer Literacy to Promote Mammography Screening among Navajo Women

Patten, Christi A., Ph.D.

Mayo Clinic, Rochester, MN

$132,301

Among American Indian and Alaska Native (AI/AN) women, breast cancer is more likely to be 

diagnosed at an advanced stage and the 5 year breast cancer survival rates are lower than any 

other ethnic group. Among Navajo women scheduled for a mammography screening 

appointment, the no show rate is markedly high (80%). This study proposes to develop a familybased cancer literacy intervention that includes culturally and linguistically appropriate education 

about breast cancer to promote mammography screening among Navajo women. This proposal 

describes a community-based participatory research study to develop and pilot test a new 

behavioral intervention to promote mammography screening among Navajo women. From a 

public health perspective, the intervention has the potential to reach many Navajo women, as 

80% of women scheduled for mammography appointments do not follow through. These women 

(over 1,500 each year) are referred to the Nation Breast and Cervical Cancer Prevention Program 

(NNBCCPP). A key barrier toward implementing cancer prevention and control efforts in the 

Navajo community is a lack of cancer literacy or cultural and conceptual knowledge regarding 

cancer. Other barriers to screening are fear of cancer, stigma of cancer (even talking about 

cancer) often experienced by the patient, family and community, and lack of knowledge about 

the etiology of cancer and importance of early detection. Therefore, communication about cancer 

is impeded within Navajo families and the community. This proposal builds on their successful 

partnership and collaboration with Dini College (the Navajo tribal college). The proposed study 

is designed to assess the feasibility and potential efficacy of a cancer-literacy focused, familybased intervention on completion of mammography screening for Navajo women. The 

intervention will include culturally and linguistically appropriate educational materials about 

cancer (e.g., the Navajo Cancer Glossary). The project will be implemented in two phases. 

During Phase 1, they will develop the family cancer literacy intervention with feedback from 

their community advisory committee. In addition, the Cancer Literacy Measure will be adapted 

for Navajo women through focus groups and individual interviews. Phase 2 will consist of a 

formative evaluation of the intervention. The NNBCCPP patient and a female family member 

will be randomly assigned in pairs to the control condition (existing NNBCCPP health education 

services, N=40 pairs) or to receive these health education services plus the family cancer literacy 

intervention (N=40 pairs). They will assess the intervention's feasibility and acceptability as 

indicated by the recruitment and retention rates and qualitative ratings of treatment acceptability. 

In addition, they will examine the effect of the intervention compared with the control group on 

the proportion of women who complete mammography screening at 3-month follow-up 

documented by NNBCCPP records. They will also examine changes in Cancer Literacy Measure 

scores from baseline to 3-month follow-up among both patients and family members. They 

expect that as a result of this project, they will have developed a replicable, feasible, and 

acceptable intervention, the efficacy of which can be tested in future large-scale randomized 

clinical trials. In addition, the adapted Cancer Literacy Measure could be used in future cancer 
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prevention and control projects within the Navajo Nation. The overall objective is to reduce 

breast cancer morbidity and mortality among Navajo women.

2 U19 GM061388-11

Pharmacogenetics of Phase II Drug Metabolizing Enzymes

Weinshilboum, Richard

Mayo Clinic, Rochester, MN

$250,000

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. 

1 R21 CA139201-01A2

Mitochondria: A Novel Genetic Modifier for Breast Cancer Risk

Zhao, Hua, Ph.D.

Roswell Park Cancer Institute Corp., Buffalo, NY

$180,248

Given the fact that mitochondrial produces energy and generate reactive oxygen species (ROS), 

inherited variations in mtDNA might represent a newly described mechanism of cancer 

predisposition. Inherited variations in mtDNA may be extremely relevant for breast cancer, as 

oxidative stress has consistently been regarded as a risk factor for breast cancer. The study will 

further their understanding of the genetic events leading to the development of breast cancer; 
Page 14 of 103

explore the genetic basis linking mitochondrial, ROS and breast cancer; find the clues for breast 

cancer racial disparity, and eventually provide a means of identifying a subgroup that are most 

likely to develop breast cancer. From a clinical perspective, the long-term application of this 

information to risk assessment and thus to the prevention and early detection of breast cancer in 

families as well as population will be significant. Somatic mutations in mitochondrial DNA 

(mtDNA) have been regarded as a hallmark of cancer. However, the role of germline variations 

(polymorphisms) in mtDNA in cancer development is largely unknown. The mitochondrial 

genome is highly polymorphic among individuals and exhibits significant geographic and racial 

difference. It has been suggested that some mtDNA variants could have adverse effect by 

increase the generation of ROS. The accumulation of those adverse effects over time may 

increase individual's cancer risk. Besides the sequence variations in mtDNA, the copy number of 

mitochondria might also affect cancer risk by disturbing crosstalk between mitochondrial and 

nucleus and consequently altering nuclear DNA stability. It has been proposed that the copy 

number of mitochondria per cell reflects the gene-environmental interactions between unknown 

hereditary factors and levels of oxidative stress. However, whether the copy number of 

mitochondria could be a predictor of human cancer development remains to be determined. 

Variability in MtDNA sequence and copy number of mitochondria might be extremely relevant 

to breast cancer because oxidative stress has been suggested to play a significant role in breast 

cancer etiology. Considerable efforts have been made to discover breast cancer susceptibility 

genes. However, few have been identified to date. The dilemma might be due to the fact that 

some of the susceptibility alleles might not reside in nuclear DNA, but in mtDNA. More 

intriguingly, the geographic and racial difference of mtDNA polymorphisms might have 

implications in breast cancer racial disparity because African American women are at 

disproportionately high risk for many oxidative stress-related medical conditions, including 

breast cancer. Therefore, the investigation of the role of mitochondrial as a predisposition factor 

of breast cancer could have significant impact. In current proposal, they plan to utilize the 

valuable biospecimens and data collected through an ongoing case-control study 

(7R01CA100598) to comprehensively investigate the associations between mtDNA 

polymorphisms/haplogroups and breast cancer risk in both Caucasian American (CA) and 

African American (AA) women. They will also examine the associations between the copy 

number of mitochondria and breast cancer risk. In further analysis, they will study whether 

mtDNA polymorphisms/haplogroups and copy number of mitochondria are associated with 

aggressive clinical characteristics of breast cancer. Because the proposed research is nested 

within an ongoing study, the objectives can be addressed in a timely and cost effective manner. 

The study will further their understanding of the genetic events leading to the development of 

breast cancer; explore the genetic basis linking mitochondrial, ROS and breast cancer; find the 

clues for breast cancer racial disparity, and eventually provide a means of identifying a subgroup 

that are most likely to develop breast cancer. Such individuals may then be targeted for specific 

intervention programs such as chemoprevention and dietary modification.

5R21CA135226-02

Brca1, Sporadic Breast Cancer And Aging Women

Avraham, Hava Karsenty

Beth Israel Deaconess Medical Center

$149,600
Page 15 of 103

By defining the targets that are altered in mutated BRCA1-linked breast and ovarian cancers and 

providing insights into the BRCA1 pathways, this study may lead to potential new therapeutic 

strategies for the prevention, early diagnosis and treatment of familial breast and ovarian cancers. 

In addition, results from this work will enhance their understanding of the molecular events that 

drive breast and ovarian cancers in aging women, and may link BRCA1 and beta-catenin to 

oxidative stress and breast oncogenesis. The risk of developing breast cancer increases as 

women get older. The maintenance of DNA represents a fundamental and continuous challenge 

to every cell in the body. Genomic instability is a hallmark of most cancers as well as a hallmark 

in aging. Recent evidence strengthened the link between the maintenance of genome integrity, 

cancer susceptibility and aging. These conditions can be caused by germline mutations in 

BRCA1, which is an essential caretaker protein in the surveillance of DNA damage. Impaired 

oxidative stress response plays an important role in breast oncogenesis. Beta-catenin was shown 

to be a co-factor for the FOXO family, which promotes survival by inducing cell cycle arrest and 

quiescence in response to oxidative stress. They observed that wild-type (WT) BRCA1, but not 

mutated BRCA1, interacts with beta-catenin and increases beta-catenin protein expression by 

promoting lysine-6-linked ubiquitination. Oxidative stress reagent H2O2 increased 

colocalization and the interaction of BRCA1 with beta-catenin in the nucleus. WT-BRCA1, but 

not mutated BRCA1, protected the nuclear active form of beta-catenin during oxidative stress 

responses. The expression of this form of beta-catenin was lower or absent in most of BRCA1 

familial breast cancer tissues. Therefore, they hypothesize that: 1) BRCA1 acts as a sensor in 

regulating beta-catenin mediated oxidative stress and FOXO function; and 2) low expression of 

WT-BRCA1 or mutations in BRCA1 leads to impaired response to oxidative stress and causes 

genomic instability, resulting in increased risk of breast cancer in women. Therefore, they aim to 

examine the effects of BRCA1 on beta-catenin protein expression and stability and to analyze the 

role of BRCA1 in beta-catenin mediated oxidative stress response. Thus, they specifically 

propose the following aims: Aim 1: To investigate the role of Brca1 in the expression and 

distribution of beta-catenin and its targets (cyclin D1 and c-Myc) during mammary gland 

development in Brca1 mutant mice, in which Brca1 exon 11 is specifically deleted from the 

mammary glands by using the Cre-loxP system. Aim 2: To characterize the role of BRCA1 as a 

sensor in regulating the beta-catenin and FOXO interaction during oxidative stress signaling. 

Results from this work will enhance their knowledge of the molecular events that drive sporadic 

breast and ovarian cancer development and progression in aging women.

5R21CA140936-02

Improving Flexible Sigmoidoscopy In Women By Optical Analysis Of Microvasculature

Backman, Vadim

Northshore Univ Health system Res Inst

$167,750

Flexible sigmoidoscopy as a colorectal cancer screening test is widely available but inaccurate at 

detecting premalignant polyps in women, largely because women's polyps tend to be located out 

of reach of the flexible sigmoidoscope. They believe that assessing the superficial blood supply 

in the visually normal rectum may be uniquely able to sense these lesions further up in the colon 

of women. If successful, this relatively inexpensive, easy-to-use test may be an adjunct to 

flexible sigmoidoscopy thereby allowing accurate and cost-effective colorectal cancer screening 

for women. Despite a myriad of screening tests available, colorectal cancer (CRC) remains the 

second leading cause of cancer deaths among Americans. Approximately half the population 
Page 16 of 103

does not undergo any CRC screening because of cost, access and concerns about discomfort with 

both the procedure and colonic purge. Flexible sigmoidoscopy (endoscopic evaluation of the 

distal colon) is performed in the community and has many advantages over other recommended 

tests (e.g. colonoscopy, CT colography) such as being relatively inexpensive, more widely 

available (performed by primary care physicians) and proven efficacy at decreasing both CRC 

mortality and incidence. However, flexible sigmoidoscopy is insensitive in women given their 

predilection for proximal neoplasia. Indeed, while flex sig identifies two-thirds of advanced 

adenomas in men, it only detects one-third in women highlighting the need for adjunctive 

approaches. Their multi-disciplinary CRC prevention group has focused on bridging novel 

optical technologies to clinical practice. Using 4-dimensional elastic light scattering 

fingerprinting (4D-ELF), they published that in CRC models, the peri-cryptal capillary blood 

content was increased prior to any histological abnormalities (a phenomena they termed EIBS 

(early increase in blood supply). They developed an endoscopically- compatible fiber-optic 

probe and demonstrated that EIBS was detectable at a distance from neoplastic lesions. In the 

rectum, EIBS was detectable in patients harboring advanced neoplasia elsewhere in their colon. 

Importantly, rectal EIBS was more robust in women (~60% increase versus neoplasia-free 

controls) than men (~25%) for proximal advanced neoplasia (that was not visualizable by 

flexible sigmoidoscope). They, therefore, hypothesize that rectal EIBS measurement will detect 

advanced proximal neoplasia in women. They will obtain rectal EIBS analysis on women 

undergoing colonoscopy. They will identify diagnostic EIBS parameters and determine the 

impact of demographic factors (e.g. age, race, smoking, medication use) on these markers. This 

data will be used to formulate a prediction rule for advanced proximal adenomas. They will then 

prospectively validate this prediction rule on a separate cohort of women simulating real world 

flexible sigmoidoscopy screening conditions prior to full colonoscopy. This will provide the 

rationale to performing future multi-center trials of rectal EIBS as an adjunct to flex sig in 

women. If successful, this practical and relatively inexpensive approach may be pivotal for the 

resurgence of flexible sigmoidoscopy as an accurate, cost-effective and patient-friendly CRC 

screening option in women.

5R21CA135532-02

Regulation Of Breast Cancer Progression By Fak Expression In Tumor Macrophages

Bouton, Amy H

University Of Virginia Charlottesville

$164,700

By focusing on the role of FAK in both macrophages and tumor cells, this work will uncover 

novel features of macrophage - tumor cell synergy that contribute to breast tumor behaviors. In 

addition to providing critical information about how FAK inhibitors should be used to treat 

breast cancer patients, this work will potentially identify new strategies for targeting distinct 

cellular compartments within the tumor that can be exploited therapeutically to control tumor 

growth and progression. It is anticipated that, through the knowledge gained from these studies, 

there will be a significant reduction in mortality from breast cancer. The growth and metastatic 

spread of solid tumors is controlled by signals emanating from tumor cells as well as by immune 

cells and fibroblasts in the surrounding stroma, components of the extracellular matrix, and 

soluble growth factors and cytokines. While this complexity creates challenges for therapeutic 

intervention, it also provides unique opportunities by making available a number of distinct 

cellular and molecular targets that can be exploited to control tumor growth and progression. The 
Page 17 of 103

focus of this proposal is on Focal Adhesion Kinase (FAK), a protein tyrosine kinase whose 

expression is significantly increased in many late-stage cancers, including breast cancer. They 

hypothesize that FAK expression in two components of the tumor microenvironment, the tumor 

cells and tumor-associated macrophages (TAMs), plays a critical role in promoting breast tumor 

progression and metastasis. They will use mouse models of breast cancer to gain an 

understanding of how FAK expression in breast carcinoma cells and/or the ancillary tumorassociated macrophages controls primary breast tumor growth and metastatic spread. By 

combining genetic manipulation of these mice with FAK inhibitors currently in Phase I clinical 

trials, they propose to 1) determine how the loss of FAK expression in macrophages alters or 

ablates macrophage functions that drive breast tumor growth/progression and metastasis (Aim 

1); 2) assess how the dual modulation of FAK expression in breast tumor cells and in tumorassociated macrophages alters breast tumor growth and metastasis (Aim 2A); and 3) assess how 

systemic inhibition of FAK expression alters breast tumor growth and metastasis (Aim 2B). 

Successful completion of this study will provide new insights into features of the tumor that can 

predict a clinical response to the FAK-targeted drugs currently in clinical trials and the optimal 

timing for these treatments. More globally, they will learn about mechanisms through which 

tumor cells and other cells within the tumor microenvironment communicate to promote breast 

tumor growth and metastasis. They anticipate that this work will help to move the paradigm for 

breast cancer treatment away from the tumor cells per se and toward the full complement of 

factors that contribute to tumor growth and metastasis.

5R21CA135237-02

Chemoprevention Of Tamoxifen-Induced Endometrial Cancer By Black Cohosh And Red C

Dietz, Birgit Maria

University Of Illinois At Chicago

$172,698

The selective estrogen receptor modulator, tamoxifen, is very effective in treatment and 

prevention of breast cancer; however, it causes menopausal symptoms and has carcinogenic 

effects on the endometrium. They hypothesize that red clover and black cohosh, both frequently 

used for the alleviation of menopausal symptoms, will reduce tamoxifen-induced endometrial 

cancer due to their cancer chemopreventive properties. Chemoprevention of Tamoxifeninduced Endometrial cancer by black cohosh and red clover Breast cancer is the most common 

cancer in women. The selective estrogen receptor modulator tamoxifen, which antagonizes 

estrogen in breast tissue, is efficacious in the treatment and prevention of breast cancer. In 

tamoxifen treated patients, botanical dietary supplements such as red clover and black cohosh 

extracts are frequently used for the alleviation of tamoxifen related menopausal symptoms. Very 

few studies about the modifying effects of these botanicals on tamoxifen's safety and efficacy 

have been reported. Tamoxifen's major side effect is an enhanced endometrial cancer risk. 

Tamoxifen's ER1 mediated uterotrophic activity and its reactive metabolites are believed to be 

responsible for this effect. Black cohosh and red clover contain anti-oxidative, anti-proliferative, 

anti-inflammatory, and detoxification enzyme inducing compounds, which could inhibit the 

initiation or retard the promotion and progression of cancerous cells. The central hypothesis of 

this project is that black cohosh and red clover reduce the carcinogenic effects of tamoxifen on 

the endometrium by inhibition of cell proliferation (Aim I) and through enhancing detoxification 

pathways (Aim 2). To support this hypothesis they propose the following specific aims: 1. What 

is the effect of red clover or black cohosh on tamoxifen-stimulated endometrial cancer? Recent 
Page 18 of 103

data suggest that black cohosh and red clover can attenuate tamoxifen-stimulated endometrial 

cancer growth by inhibiting cell proliferation. They will measure the influence of these 

botanicals on tamoxifen stimulated endometrial tumor growth in ovariectomized athymic nude 

mice, an established endometrial cancer model for studying estrogenic influences. The 

mechanism of interaction will be examined by analyzing the expression of pro-proliferative 

genes and proteins important for tamoxifen mediated tumor promotion in vivo and in vitro. To 

further identify active compounds, they will examine the anti-proliferative effect of isolated 

compounds in endometrial cancer cells and in an immature rat model. 2. What is the effect of 

black cohosh or red clover on detoxification pathways of reactive tamoxifen metabolites? Their 

data indicate that both botanical upregulate the cellular antioxidative response machinery, thus 

reducing the carcinogenic effect of tamoxifen's reactive metabolites. They will study the ability 

of these botanicals to induce the detoxification enzymes, quinone reductase and glutathione-Stransferase, in the uterus and liver of adult rats. They will also analyze whether black cohosh and 

red clover prevent tamoxifen induced oxidative stress in these animals. Additionally, they will 

examine the effect of the botanicals on tamoxifen's metabolism to active or reactive metabolites 

in the blood. To elucidate the compounds responsible for the various effects, isolated 

constituents will be assayed in vitro. The completion of these specific aims will provide an 

overall picture of the effect of these botanicals and purified compounds on the efficacy of 

tamoxifen and on tamoxifen induced endometrial cancer, which is of importance considering the 

increasing number of breast cancer survivors and women at high risk undergoing tamoxifen 

treatment.

5R21CA135303-02

Nir Hypoxia Imaging Of Breast Tumor Response To Neoadjuvant Chemotherapy In Vivo

Jiang, Shudong

Dartmouth College

$173,800

This project will develop and evaluate dynamic Near-Infrared (NIR) tomographic oximetry for 

characterizing the response of locally advanced breast cancers to neoadjuvant chemotherapy by 

assessing the temporal variation in tumor oxygenation during hyperoxic gas inhalation. NIR 

oximetry acquired longitudinally during the course of therapy will be correlated with 

pathological endpoints in order to determine whether early prognostic biomarkers of treatment 

response can be identified in the dynamic NIR oxygenation signatures that could be used to 

customize breast cancer treatment decisions to individual patients in the future. Near-infrared 

(NIR) multi-spectral imaging is a unique tool for characterizing tissue composition in the female 

breast. The major advantage of this modality is its ability to provide images of tissue oxygen 

saturation (StO2) as well as total hemoglobin concentration (HbT), water fraction (H2O%) and 

elastic scattering parameters. Because microcirculation and oxygenation play such major roles in 

tumor progression and regression, assessing their variation in response to neoadjuvant 

chemotherapy may reveal early prognostic biomarkers of treatment response that could be used 

to alter and/or optimize the course of treatment on a more individualized patient basis. Assessing 

dynamic contrast enhancement in tumor oxygenation after hyperoxic gas inhalation with NIR 

spectral tomography appears to be feasible and may provide easily- acquired, low cost image 

signatures for predicting therapeutic response to chemotherapy in the breast. The overall goal of 

this proposal is to develop and evaluate dynamic NIR tomographic oximetry for characterizing 

the response of locally advanced breast cancers to neoadjuvant chemotherapy by assessing the 
Page 19 of 103

temporal variation in tumor oxygenation during hyperoxic gas inhalation. They hypothesize that 

tumors with initially larger and faster changes before and after breathing 100% oxygen will have 

better clinical responses to neoadjuvant chemotherapy. This hypothesis will be quantitatively 

assessed by 1) advancing the current NIR multi-spectral tomography system to image dynamic 

oxygenation changes within the tumor, induced by breathing 100% oxygen, with a 0.1 Hz image 

frame rate, 2) quantifying the tumor oxygenation response with respect to hyperoxic inhalation at 

different times during the course of therapy, and 3) quantifying the pathological and clinical 

outcomes of response in order to test for correlation with oximetry changes recorded early in the 

treatment course. Dartmouth College, through the Norris Cotton Cancer Center at the 

Dartmouth-Hitchcock Medical Center, has significant resources to leverage in order to conduct 

the proposed study. A group of investigators which includes clinical specialists in diagnostic 

radiology, surgical oncology, medical oncology, surgical pathology and medical engineering has 

been configured to develop and evaluate technology for breast imaging for cancer detection, 

diagnosis and therapy monitoring since 1999. The proposed project is an important component of 

the research of this group. In addition to the principal investigators, Professor Shudong Jiang and 

Dr. Peter A. Kaufman, MD, (Medical Oncology), Professors Keith D. Paulsen, Brian W. Pogue 

and Dr. Wendy A. Wells, MD, (Department of Pathology) will be significant collaborators 

engaged to accomplish the proposed specific aims, as an adjunct to currently funded grants 

involving breast imaging research.

5R03CA139545-02

Targeting The Phosphoinositide Kinase Chain To Prevent Breast Cancer Metastasis

Kunz, Jeannette

Baylor College Of Medicine

$76,750

This research project employs cancer cell lines and mouse models of cancer metastasis to 

uncover the signaling mechanisms that control a cell's ability to move. The migration of cells is 

important for proper tissue formation, immune function and wound repair, but when aberrantly 

regulated can also form the basis of devastating human diseases including cancer, atherosclerosis 

and allergies. Their long-term goal is to better understand the signaling mechanisms that control 

cell migration and to use this information to develop new therapeutic approaches for the 

prevention of human disease. Breast cancer is the most commonly diagnosed form of cancer in 

women 40-55 years of age and it is the second major cause of cancer deaths behind lung cancer 

for all women. Metastatic breast cancer, where cancer cells spread by motile mechanisms and 

establish tumors at distant vital sites, is much harder to eradicate and is the primary cause of 

patient death from breast cancer. Understanding the molecular principles that determine the 

efficiency of tumor metastasis is therefore critical to the prevention and treatment of breast 

tumors. Traditional cancer therapeutics are aimed at preventing tumorigenesis of normal breast 

tissue and inhibiting growth of established cancers. However, few therapeutic strategies target 

cell migration and invasion, although the pathological deregulation of these processes is a major 

cause of morbidity associated with the disease. Cell migration and invasion are coordinately 

regulated by the small GTPase Rac1 and the localized production of the lipid 

phosphatidylinositol-4,5-bisphosphate (PI4,5P2). The hyperactivation of Rac1 signaling has been 

observed in many cancers, particularly in cancers of the breast, and this is directly linked to 

increased metastatic potential and poor patient survival. A role for PI4,5P2 signaling in cancer 

progression has so far not been reported. However, recent evidence described in the preliminary 
Page 20 of 103

studies section of this proposal has established that PIPK1a, a member of the Type I 

phosphatidylinositol-4-phosphate kinase family, which generates PI4,5P2, is a critical regulator 

of cell migration and cell-matrix adhesion. They have defined a biochemical pathway in which 

PIPK1a mediates Rac1 activation in response to integrin and growth factor signals. Rac1, in turn, 

controls signaling to downstream effectors, including a second member of the PIPKI family, 

PIPK1b, to promote the assembly of F-actin and of focal adhesion sites necessary for migration 

and invasion. These results therefore establish a pathway in which PIPK1a is the pinnacle of a 

signaling cascade that links transmembrane receptors to the regulation of actin and focal 

adhesion assembly during cell motility. Because cell migration and adhesion are critical for 

cancer metastasis, PIPK1a may be a target for the prevention of cancer progression. The longterm goal of these studies is to validate PIPK1a as a target for therapeutic intervention in 

metastatic disease using tissue culture cell models and the athymic nude mouse model of breast 

cancer. The proposed research also involves pilot studies designed to assess the efficacy of a 

newly identified natural small-molecule inhibitor of PIPK1a in the control of breast cancer 

progression. They will use a combination of basic research, chemical genetic and in vivo 

approaches to systematically address the role of the PIPK1a pathway in cell migration and 

invasion in a 3-dimensional matrix, in anchorage-independent growth, and in cancer progression 

in vivo using the athymic nude mouse. The proposed research not only has the potential to 

impact therapeutic design to prevent breast cancer metastasis, but will also advance their 

understanding of signaling mechanisms that may be critical for breast cancer metastasis.

5R21CA140916-02

Mitochondrial Catalase As A Treatment For Metastatic Breast Cancer

Ladiges, Warren C.

University Of Washington

$205,823

The project is designed to determine the ability of mitochondrially targeted catalase to suppress 

metastatic breast cancer in mice. The chance of developing invasive breast cancer during a 

woman's lifetime is approximately 1 in 8 and more than 40,000 women die of metastatic disease 

each year. Inherent or acquired tumor drug resistance and dose-limiting toxicity limit many 

agents used in the treatment of invasive breast cancer. Therefore, an important goal is the 

development of novel non-toxic therapeutic agents that are active against this deadly disease. 

They have preliminary data showing that mitochondrial catalase (mCAT) reduces metastatic 

progression of primary breast cancer in mice, suggesting that targeting mitochondria with 

catalase could be a potential strategy to treat or prevent metastatic breast cancer in women. The 

aims of this proposal are 1) to further characterize the ability of mCAT to suppress breast cancer 

metastasis in mice; and 2) develop an inducible system in mice for controlling the expression of 

mCAT in a time and cell dependent manner. The data generated in this proposal would confirm 

their preliminary observations and provide the rationale for developing and/or testing clinically 

relevant mitochondrial-specific drug delivery systems for treating metastatic breast cancer.

5R21CA141112-02

Gender Selectivity To Colon Cancer Chemoprevention By Nsaids

Roy, Hemant K

Northshore Univ Health system Res Inst

$167,750
Page 21 of 103

Colorectal cancer is one of the major public health issues in US with life time risk of being 

diagnosed with this cancer is about 6%. This cancer usually develops slowly (10- 15 years) 

through multiple genetic and phenotypic transitions from normal colonic mucosa to adenoma and 

then to carcinoma. This protracted progression provides ample time for interventions such as 

endoscopic screening and removing adenomatous polyps. This has been promising but only 

about half of the at-risk population (age >50) receive any sort of effective screening. This 

underscores the need for developing alternate cancer prevention strategies such as 

chemoprevention. Number of studies shows that nonsteroidal anti-inflammatory drugs 

(NSAIDS) exert chemopreventive benefits against CRC. However, the overall efficacy is 

relatively modest (30-50% risk reduction) and requires more than a decade to show significant 

benefits. In addition, the use of NSAIDS has been shown to be linked to severe side-effects 

including ulcers, GI bleeding, hemorrhagic strokes etc, thereby causing some uncertainty in its 

use for preventing CRC for average risk use. To improve the risk-benefit analysis, it is therefore 

critical to selectively target subjects that can efficiently respond to chemopreventive efficacy of 

nonsteroidal anti-inflammatory drugs (NSAIDS). It has recently been shown that women with 

CRC may respond to dietary nutrients or pharmacological agents differently than men as they 

may have differing pathologies, risk factors and hormone status. The epidemiological studies 

suggest an improved chemopreventive response in women to NSAIDS although there are 

discordant reports in the literature. Thus, the issue of whether women are more sensitive to 

NSAID chemoprevention is unresolved with possibility that NSAIDS type, dose etc may play a 

role. The proposed studies will address the role of estrogen in gender selective chemopreventive 

efficacy of NSAIDS. These findings will have an important bearing on the healthcare 

recommendations for colon cancer chemoprevention which have to be cognizant of this gender 

selective efficacy for maximum cost-benefit potential of NSAIDS. Colorectal cancer (CRC) is 

the second leading cause of cancer deaths among Americans. With proper screening and removal 

of adenomatous polyps, CRC risk reduction has been very promising. However, only ~50% of 

the at-risk population (age >50) receives any sort of screening and many undergo tests with 

suboptimal sensitivity. This underscores the need for developing alternate cancer prevention 

strategies such as chemoprevention. Of the myriad of purported agents, nonsteroidal antiinflammatory drugs (NSAIDS) have reliably shown a positive outcome. Indeed, epidemiological, 

experimental and clinical trials unequivocally point to the CRC preventive benefits of NSAIDS. 

However, the efficacy is relatively modest (30-50% risk reduction) and requires more than a 

decade to show significant benefits. In addition, the use of NSAIDS has been shown linked to 

severe side-effects including ulcers, GI bleeding, hemorrhagic strokes etc, thereby cautioning 

that the risks may outweigh the benefits of aspirin and NSAIDS in preventing CRC for average 

risk use. To improve the risk-benefit analysis, it is therefore critical to selectively target subjects 

that can efficiently respond to chemopreventive efficacy of NSAIDS and at the same time leave 

out the population least likely to benefit. It is conceivable that responsive patients could be 

targeted with lower efficacious doses to avoid associated toxicity. Gender is an important risk 

factor for CRC with women frequently having biological differences (higher prevalence of 

proximal lesions, DNA mismatch repair deficient tumors etc). Estrogen is a well-accepted 

chemopreventive agent against CRC. Moreover, their group has reported that women have 

altered susceptibility to both genetic and environmental CRC risk factors. The epidemiological 

data has some studies suggesting an improved chemopreventive response to NSAIDS although 

there are discordant reports in the literature. Thus, the issue of whether women are more 

sensitive to NSAID chemoprevention is unresolved with possibility that NSAID type, dose etc 
Page 22 of 103

may play a role. They recently conducted a chemoprevention trial using the NSAID celecoxib in 

a well-validated model of intestinal tumorigenesis, the MIN mouse. They noted that in this 

model, females were more responsive to the chemopreventive effects of celecoxib. The 

chemopreventive response was found to have regional propensity with stronger efficacy in the 

proximal intestine. Furthermore, celecoxib treated female mice had higher levels of mucosal 

estrogen receptor-2 (ER2) levels. They hypothesize that in colorectal cancer, NSAIDS present an 

increased chemopreventive efficacy in females which may be secondary to modulation of 

estrogen receptor ER2 expression.

5R21CA134882-02

Antagonism Of The Ah Receptor In Controlling Breast Cancer Growth And Invasion

Schlezinger, Jennifer J

Boston University Medical Campus

$178,823

They hypothesize that the hyper-expression of a protein, called the aryl hydrocarbon receptor, 

and its binding to DNA contributes to the growth and progression of breast tumors. Here they 

propose that chemicals that impede the function of this receptor (i.e. antagonists) will be 

effective at downregulating this protein's activity and therefore will suppress breast tumor 

growth and metastasis. Screening of plant and marine natural product libraries will provide a 

source of novel antagonists that can be tested for their interaction with this receptor and their 

mechanism of interference with tumor growth, ultimately resulting in the development of 

therapeutic agents for the treatment of breast cancer. Historically, the aryl hydrocarbon receptor 

(AhR) has been studied for its transcriptional regulation of genes encoding cytochrome P450 

enzymes, which metabolize environmental and endogenous substrates into toxic and mutagenic 

intermediates. Accumulating studies support the hypothesis that the AhR also plays an important 

role in malignant epithelial cell growth and invasion apart from its role in formation of mutagens 

and in the absence of environmental chemicals. This new paradigm is based on several key 

observations: 1) AhR expression is increased dramatically in carcinogen-induced rat and mouse 

mammary tumors and in 'spontaneous' human mammary tumor lines. 2) Constitutive AhR 

activation is indicated by nuclear AhR localization in rat, mouse, and human mammary tumors 

and by AhR binding to gene promoters in the absence of environmental chemicals. 3) 

Constitutively active AhR regulates the expression of multiple genes, including CYP1B1, CK21, 

and Slug, a master regulator of tumor invasion. 4) Recent studies suggest that increased AhR 

activity in mammary tumors also contributes to cell migration and invasiveness. 5) Molecular 

downregulation of the AhR suppresses breast cancer cell proliferation and reverts cells to a nonaggressive phenotype. Molecular and biologic strategies have provided significant evidence that 

the AhR participates, beyond mutagenesis, in multiple mechanisms that contribute to tumor 

formation, growth and invasion. Therefore, they can exploit their ability to examine effects of 

constitutively active AhR to determine how chemical antagonism of the AhR may translate into 

breast cancer prevention or a therapeutic approach to suppress tumor progression. Thus, they 

propose a new hypothesis: Targeting the constitutively active AhR with naturally occurring, nontoxic antagonists represents a feasible therapeutic approach to inhibit breast tumor growth and 

invasion. Three specific aims are proposed: 1. Investigate strategies to maximize antagonism of 

the AhR by examining the potential for synergistic interaction in mixtures of antagonists, 

performing a high-throughput screen for novel, potent antagonists from natural product extract 

libraries (NCI Natural Products Repository) and examining the 'chemical knockout' approach for 
Page 23 of 103

improving AhR inactivation. 2. Define the molecular mechanisms of chemical antagonism of the 

constitutively active AhR in a breast cancer model by establishing antagonist effects on AhR 

transactivation of endogenous gene expression and examining antagonist-mediated changes in 

AhR-DNA interactions. 3. Establish the functional consequences of chemically antagonizing the 

constitutively active AhR using optimal AhR antagonists. The translational impact of these 

studies lies in the ability of known and newly identified antagonists to suppress tumor growth 

and invasion. Here, potentially therapeutic AhR antagonists will be evaluated for their ability to 

block the biological outcomes of constitutive AhR activity in human mammary tumor cell lines. 

Collectively, these studies will provide the foundation for preclinical studies on the potential for 

potent AhR antagonists to prevent and/or treat breast cancer in vivo.

5R03CA141564-02

Role Of Micrornas In Initiation And Progression Of Breast Cancer

Sempere, Lorenzo

Dartmouth College

$79,000

MicroRNAs are a recently-discovered class of short non-coding RNA genes, which act as posttranscriptional negative regulators of gene expression. microRNA-mediated regulation of 

tumorigenesis is emerging as a new paradigm in the field of cancer biology. Their implemented 

in situ hybridization technology offers spatial resolution of miRNA expression unsurpassed by 

other techniques, which could be readily adapted to routine clinical practice to benefit patients 

and assist physicians in making crucial decisions.Breast carcinoma (BrCa), which is the second 

most prevalent cancer in women, is a complex, inadequately understood, and often fatal disease 

when not detected at early stages. A more detailed understanding of the molecular mechanisms 

and regulatory pathways at work will enormously assist in improving the design and target 

selection of therapeutic strategies. MicroRNAs (miRNAs) are evolutionary conserved, short noncoding regulatory RNAs that post- transcriptionally modulate gene expression by binding to their 

cognate target mRNAs via pervasive and versatile mechanisms. Altered expression of specific 

subsets of miRNAs has been linked to different types of hematologic and solid tumors. 

Independent studies using BrCa clinical specimens have identified a small subset of miRNAs, 

which are differentially detected between normal and tumor tissue specimens. Thus, the clinical 

value of these miRNAs as novel biomarkers for different aspect of BrCa management is being 

actively investigated. Importantly, functional analyses in cell line systems and xenograft 

transplantation in mouse models have revealed tumor suppressive and oncogenic functions of 

some of these miRNAs. This proposal focuses on miRNAs as potential tumor suppressive 

mechanisms to prevent breast carcinogenesis. They will utilize a genetic approach in mouse 

models of BrCa to test the hypothesis that global impairment of miRNA functions enhances 

tumor growth and aggressiveness. Of note, their experimental strategy will be similar to the one 

successfully used by Tyler Jacks and colleagues to uncover tumor suppressive roles of miRNAs 

in a K-Ras-driven mouse model of lung cancer. They will target chromosomal deletion of 

miRNA- processing enzyme Dicer in mammary gland epithelia using the Cre/LoxP system. The 

effects of global loss of miRNA functions will be studied in well-established mouse models of 

BrCa. Mammary gland restricted expression of Polyoma virus middle T antigen (PyMT), 

Neu/HER-2 or Wnt-1 causes BrCa with different latencies and histological features reminiscent 

of specific human BrCa subtypes. They expect that results of this proposal will uncover an 

etiological contribution of miRNAs and validate the use of these mouse models for future studies 
Page 24 of 103

concentrating on the role of individual miRNA in BrCa and development of miRNA-based 

therapeutic strategies.

5R21CA142537-02

Reactivation Of Breast Cancer Micrometastases By Senescent Bone Marrow Stroma

Wieder, Robert

Univ Of Med/Dent Of NJ- Medical School

$171,600

The proposed study will investigate the induction of senescence in mouse bone marrow stroma 

by estrogen deprivation in vitro and in vivo as manifested by the secretion of inflammatory 

cytokines and loss of the capacity to support dormancy of breast cancer cells in an in vitro model 

and the loss of the capacity to support the dormancy of xenografted human breast cancer cells in 

the bone marrow microenvironment. Experiments will determine if treatment with estrogen or 

anti-inflammatory agents can restore the capacity of senescent stroma to support dormancy. 

More than a third of stage I-III breast cancer patients have bone marrow micrometastases at the 

time of diagnosis providing a source of recurrence. Most recurrences occur in post-menopausal 

women. Mechanisms of dormancy and recurrence are not well understood, but data suggest a 

dependence on a close association with bone marrow stroma. They hypothesize that stromal cells 

undergo senescence due to aging and/or post-menopausal estrogen deprivation and begin to 

secrete inflammatory cytokines that can stimulate dormant cancer cells to re-awaken. The broad, 

long-term goals of their investigations are to define mechanisms that govern the establishment of 

the dormant state in breast cancer cells in the bone marrow and to determine factors and 

mechanisms responsible for their re-awakening and recurrence of disease. They propose to 

determine if bone marrow stroma can undergo senescence when deprived of estrogen or treated 

with cytotoxins in vitro and in vivo in a murine model. Their specific aims are: 1. to determine if 

in vitro estrogen deprivation can induce a senescent phenotype in bone marrow stromal cultures 

incapable of supporting breast cancer dormancy in an in vitro model and 2. to determine if in 

vivo estrogen deprivation induces a senescent phenotype in bone marrow stroma rendering it 

incapable of supporting breast cancer dormancy in vitro and in vivo. They will establish and 

characterize the phenotype of secretory senescence by subjecting stromal monolayers to 

oxidative and hypoxic stress and estrogen deprivation and measure the expression and activation 

of TGF¿, Cox-2, IL-6, IL-8 and SA-¿Gal, known markers associated with senescence. They will 

determine if estrogen deprivation in vitro and in vivo and cytotoxicity in vitro can induce 

senescence measured by these molecular markers and by the loss of support of breast cancer 

dormancy in an in vitro clonogenic co-culture model and in a left ventricle injection bone 

marrow metastasis model. Experiments will also determine whether estrogen-deprivation renders 

stroma more susceptible to chemical injury and whether administration of Cox-2 inhibitors or 

estrogen can reverse these effects. These studies will establish a way of thinking about dormancy 

as a function of the senescent microenvironment and seek to reverse estrogen-deprivationinduced inflammation to maintain it.

5R21AI079439-02

Hpv Epidemiology And Response To Screening (Hearts)

Riley, Elise D

University Of California San Francisco

$156,969
Page 25 of 103

To the best of their knowledge, this is the first study regarding HPV and HPV disease among 

homeless and marginally housed women. Ascertaining prevalence and risk factors specific to this 

population will facilitate a better understanding of HPV among indigent US women, which could 

have implications for improvement in health care delivery, particularly regarding HPV vaccine 

uptake and effectiveness. Given that poor and marginally housed women use health services 

infrequently, the potential benefits of a prophylactic vaccine are of the utmost importance. HPV 

vaccine development and clinical research have focused on women from the general population 

and little is known about HPV among indigent women, many of whom experience repeated risk 

for sexually transmitted infections that continues through the span of their lives. The impact of 

repeated exposure to HPV, as well as the impact of co-infections like HIV, HCV, gonorrhea, and 

Chlamydia, on the natural history of HPV infection and HPV-associated disease, is unclear in 

this population. Moreover, the prevalence of HPV subtypes in this population is unknown, which 

precludes estimates of potential vaccine effectiveness. A better understanding of HPV among 

indigent US women could have implications for improvement in health care delivery, 

particularly regarding HPV vaccine uptake and effectiveness. They propose an exploratory study 

to assess the prevalence and variability of cervical HPV and cervical HPV disease (cervical 

intraepithelial neoplasia); associations with co-infections (i.e., HIV, HCV, gonorrhea and 

Chlamydia) and drug use (e.g., tobacco and crack cocaine); and the feasibility of a larger 

randomized study among homeless and marginally housed women. Individuals will be recruited 

from homeless shelters, free food programs and low-income single room occupancy hotels. In 

this way, study participants will not be limited to individuals who visit specific institutions, thus 

facilitating reliable estimates from a community-based sample.

CHRONIC FATIGUE SYNDROME

5 R01 AR053821-04

HERV-K18 as a Risk Factor for CFIDS

Huber, Brigitte T.

Tufts University Boston

Boston, MA

$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 
Page 26 of 103

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.

CARDIOVASCULAR DISEASE

5R21HL093450-02

Compromised Microcirculation In Women With Polycystic Ovary Syndrome

Stachenfeld, Nina

John B. Pierce Laboratory, Inc.

$223,143

Women with Polycystic Ovary Syndrome (PCOS) have greater risk for cardiovascular disease, in 

particular dysfunction of the peripheral circulation that can lead to hypertension and comprised 

glucose disposal. This research will determine the role of hyperandrogenism in microvascular 

responsiveness in women with PCOS, and the mechanisms by which testosterone may impact 

endothelial function. These studies also have broad public health implications because their 

findings on the effect of hyperandrogenism on endothelial function may provide insights that can 

improve cardiovascular health of all obese women and men. Polycystic ovary syndrome 

(PCOS) is the most common reproductive endocrinopathy in young women, affecting 6-10 % of 

women of reproductive age. Obesity, insulin resistance, hyperandrogenism and hyperestrogenism 

are core functional disorders of PCOS and place women at increased risk for microvascular 

dysfunction. Women with PCOS have greater circulating concentrations of endothelin-1 (ET-1), 

a potent vasoconstrictor in the microcirculation (including that of the skin), which can increase 

blood pressure and lead to endothelial damage. The central hypothesis of this proposal is that 

testosterone effects on ET-1 mediate the peripheral microvascular dysfunction associated with 

PCOS. This hypothesis will be tested using a prolonged skin heating model to study peripheral 

microvascular responsiveness. Local skin heating has been used extensively to study 

mechanisms controlling peripheral microcirculation under a number of physiological conditions, 

including obesity, insulin resistance and hypertension. The impact of testosterone or ET-1 on 

microvascular responsiveness to local heating has not been studied in women with or without 
Page 27 of 103

PCOS. This proposal seeks to provide this missing information via pursuit of two Specific Aims. 

Specific Aim 1 will apply dose-response curves to examine the mechanism by which ET-1 

influences peripheral vasodilation. Specific Aim 2 will determine the mechanism by which 

testosterone affects peripheral microcirculatory responsiveness in women with and without 

PCOS. These studies will have broad public health implications because their findings on the 

effect of hyperandrogenism on endothelial function may provide insights applicable to 

cardiovascular health in women and men.

5R21HL093665-02

Sex Differences In Myocardial Ischemia Triggered By Emotional Factors After Mi

Vaccarino, Viola

Emory University

$193,750

Coronary heart disease is the major cause of death in American women and yet, much remains to 

be learned about the unique characteristics of this disease in women. Young and middle-aged 

women have higher mortality and complication rates after an acute myocardial infarction (MI) 

and higher burden of psychosocial risk factors. This study will evaluate whether emotionally 

triggered ischemia is more common in women than in men after MI, whether it is correlated with 

psychosocial risk factors that are common in women, such as depression and history of trauma, 

and whether it is associated with biological changes that may have prognostic significance, such 

as hemodynamic, neurobiological and inflammatory responses to stress. Coronary heart disease 

(CHD) is the major cause of death in American women, and every year a similar number of 

women and men die due to CHD. Growing evidence supports important differences in the 

pathophysiology, clinical presentation and prognosis of CHD between women and men; yet 

much remains to be learned about the unique characteristics of CHD in women. Young and 

middle-aged women have higher mortality and complication rates after an acute myocardial 

infarction (MI) compared with men of similar age. Reasons for these differences are unknown; 

they are not explained by traditional CHD risk factors, other comorbidity or treatments, and 

occur despite the fact that women have less coronary atherosclerosis and more preserved 

ventricular function than men. One third to two thirds of patients with CHD have myocardial 

ischemia that is induced by psychological stressors. Such ischemia is often painless and 

unrelated to severity of coronary artery disease; nonetheless it is associated with adverse 

outcomes. Emotional factors such as depression and psychological trauma are more common in 

women with CHD than in men and may predispose women to stress-induced ischemia. 

Depression, for example, is present in up to 40% of women with MI younger than 60 years. 

However, emotionally-triggered ischemia has hardly been studied in women before. The overall 

objective of this proposal is to evaluate differences in stress-induced ischemia between 50 

women and 50 men younger than 60 years who were hospitalized for acute MI in the previous 6 

months in Emory- affiliated hospitals. They hypothesize that myocardial ischemia due to 

emotional factors is more common in women than in men, while exercise-induced ischemia is as 

common, or even less common, in women. The aims of this study are: (1) Using single photon 

emission tomography (SPECT) [Tc-99m] sestamibi myocardial perfusion imaging, to compare 

myocardial perfusion during rest, during exercise, and during an emotionally stressful challenge 

in women and men. (2) To investigate biological mechanisms for the sex differences in ischemia 

induced by emotional stress, including differences in hemodynamic (blood pressure, heart rate), 

neurobiological (cortisol and autonomic nervous system) and inflammatory responses to the 
Page 28 of 103

stressful challenge. (3) To investigate behavioral/psychosocial explanatory factors for the sex 

differences in ischemia induced by emotional stress (depression, history of trauma, and socioeconomic environment). Younger women with MI represent an understudied patient group 

despite their higher rate of adverse events compared with men. Investigation of this group will 

provide critical information for the prevention of CHD in women. Their study may uncover a 

unique pathway which may explain sex differences in the outcome of MI.

5 R01 TW008288-02

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 

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 they 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. 
Page 29 of 103

5 R21 HL093626-02

Mechanisms Underlie Inverse Gender Discrepancy in Ischemic Protection

Shi, Nian-Qing

University of Wisconsin Madison, Madison, WI

$185,625

The proposed research will employ KATP channel mutant mice that are defective in the 

sulfonylurea receptor 2 (SUR2) to evaluate gender difference in ischemic protection, regulation 

of estrogen in sarcolemmal and mitochondrial SUR2 forms and obtain new insights in ion 

channel regulation in cardiovascular diseases. Myocardial infarction (MI) is a major health 

problem worldwide due to its acute nature and lack of effective prevention schemes. Gender 

difference in ischemic protection exists, with relatively lower MI incidences in pre- menopausal 

females than age-matched males. Emerging evidence indicates that the female-specific 

advantage in ischemic protection is mediated by estrogen. In the ischemic protection network,

KATP channels (KATP) are postulated to play protective roles, but their relative importance 

remains to be controversial. Composed by a Kir6.2 pore and an SUR2 regulatory subunit, KATP 

activity is recorded in cardiac sarcolemmal or mitochondrial inner membrane. their recent data 

show that disrupting the SUR2 gene at an earlier exon 3 causes an early lethality and the mutants 

only lived 8 days. However, disrupting SUR2 at middle exons 12-16 interrupts the SUR2 long 

forms, but the novel SUR2 short forms remain expressed. They have identified 2 splice variants 

that are generated by a rare intra-exonic splicing (IES) event in SUR2 mRNA to produce 

transcripts encoding the 55-kDa SUR2 short forms in heart mitochondria. Characterization of 

SUR2 KO has revealed an inverse pattern of gender difference in cardioprotection. Completed 

tests in KO males show that they are constitutively protected, with reduced infarcts after 

ischemia, while KO females have larger infarcts and cannot be preconditioned. mRNA levels of 

both IES variants markedly increase in the preconditioned KO males but they reduce 

dramatically in the preconditioned KO females. This interesting discrepancy offers a new 

platform of using SUR2 mutant mice to investigate gender difference in ischemic protection. The 

proposed research intends to explore the molecular mechanisms underlying gender difference in 

cardioprotection in relation to KATP channels, especially mitochondrial KATP. They

hypothesized that estrogen modulates expression of sarcolemmal and mitochondrial SUR2 forms 

in mice. They further hypothesized that levels of the IES variants encoding the mitochondrial 

SUR2 short forms are critical to protection. In Aim 1, they will characterize ischemic protection 

in both genders of WT and KO mice, and study whether estrogen modulates expression of the 

SUR2 forms. In Aim 2, estrogen regulation in mitochondrial SUR2 will be investigated, and a 

55A "rescued" female mouse model will be tested whether they can improve protection. 

Interactions of estrogen receptor 2 and the IES variants will be explored. Results from this 

research not only provide new insights in gender-specific response to cardioprotection but also 

identify new drug targets for future clinical treatments against MI. 

CRANIOFACIAL

3-U01-DE-017018-06S2

Risk Factors for Onset and Persistence of TMD

Maxiner, William

University of North Carolina, Chapel Hill, NC
Page 30 of 103

$150,000

Risk factors for onset and persistence of TMD: Myogenous temporomandibular disorder (TMD), 

with or without arthralgia, ranks second only to headache as the clinical condition most likely to 

cause craniofacial pain and dysfunction in the U.S. population. During the last decade, a small 

number of epidemiological studies have attempted to quantify the incidence of TMD in 

populations of European heritage; however, no investigative team to date has undertaken a largescale, hypothesis-driven, prospective study designed to identify biopsychosocial and genetic risk 

factors for the onset and persistence of this vexing pain disorder. They propose to conduct a 

comprehensive, prospective cohort study of the incidence of TMD in collaboration with an 

internationally recognized group of epidemiologists, pain researchers, and geneticists. 

Participants will be enrolled and followed prospectively at four research institutions and by their 

Data Coordinating Center (Battelle Memorial Institute). their three goals are to: a) undertake a 

five-year, prospective cohort study of 3200 initially TMD-free individuals recruited from major 

ethnic and racial strata at four study sites, quantifying incidence rates of first-onset-TMD; b) 

undertake a case-control study by recruiting 200 people with chronically symptomatic TMD 

identified during cohort recruitment whose history of TMD precludes them from the prospective 

study; c) to identify in both groups the individual and joint effects of predictors of TMD risk 

using a conceptual, causal model for TMD that they have developed based their own studies and 

other published research. Their preliminary epidemiological findings have led to the central 

hypothesis that pain amplification and psychological factors, both of which are influenced by 

genetic variants, represent causal risk factors that influence TMD onset and persistence. The 

outcomes of their proposed study will identify the primary socio-demographic, clinical, 

biological, psychological, and genetic risk factors for TMD onset and persistence. In so doing, 

they will obtain important and novel information regarding the etiopathogenesis of TMD, which 

will assist with the development of evidenced based pharmacological and behavioral 

interventions for TMD.

DIABETES

5R21HL093699-02

Gender Specific Complications Of Diabetic Autonomic Neuropathy: A New Mouse Model

Galper, Jonas Bernard

Tufts Medical Center

$198,750

Diabetic Autonomic Neuropathy (DAN) is characterized by impairment of autonomic 

responsiveness of the heart and an increased incidence of arrhythmia and sudden death. Data 

suggest the hypothesis that menopausal women might be more likely to develop DAN and that 

hormone replacement therapy might protect the heart from development of DAN and decrease 

the incidence of arrhythmia and sudden death. Here they propose to test the hypothesis that the 

female Akita mouse might serve as an animal model for the study of Gender Specific 

Complications of DAN and the protective effects of estrogens against the development of 

diabetes and its secondary complications in the heart. Diabetic Autonomic Neuropathy (DAN) 

is characterized by impairment of autonomic responsiveness of the heart. DAN has been 

associated with an increased incidence of arrhythmia and sudden death in diabetics. Although the 

overall incidence of sudden death is lower in women than in men, the risk of sudden death 
Page 31 of 103

associated with diabetes in women is greater than in men. Studies in postmenopausal women 

demonstrated that combined estrogen/progestin therapy reduced the incidence of diabetes. 

Comparison of heart rate variability showed that the parasympathetic response of the heart was 

increased in young women compared with men; this difference was attenuated after menopause, 

but maintained in women on hormone replacement therapy (HRT). These data suggested the 

hypothesis that menopausal women might be more likely to develop DAN and that HRT might 

protect the heart from development of DAN and decrease the incidence of arrhythmia and 

sudden death. The Akita mouse manifests a gender difference in the development of diabetes: 

males develop severe hyperglycemia and secondary effects of diabetes, while females exhibit 

only a mild hyperglycemia. Using male Akita mice, they have previously developed an animal 

model for DAN that is characterized by the appearance of spontaneous ventricular arrhythmias 

following myocardial infarction (MI). Here they propose to test the hypothesis that the female 

Akita mouse might serve as an animal model for the study of Gender Specific Complications of 

DAN. Specifically, they will test the hypotheses 1) that ovariectomy of female Akita mice results 

in the development of the diabetic phenotype and secondary effects of diabetes as demonstrated 

by the development of hyperglycemia, proteinuria and a decreased parasympathetic inhibition of 

Isoproterenol-stimulated L-type Ca2+ currents, and that estrogen reverses this effect 2) that 

estrogen replacement protects ovariectomized female Akita mice against the development of 

spontaneous ventricular arrhythmias following MI and 3) that gene array studies will establish a 

subset of genes that are differentially expressed in ovariectomized mice who develop 

arrhythmias following MI, which might serve as candidate genes for the treatment and 

prevention of this effect of diabetes in women. Studies in this application propose to establish a 

unique animal model, which might offer a new gender specific therapeutic approach to diabetes 

and the complications of DAN.

5-U01-DK-057136-12

Look AHEAD: Action for Health in Diabetes

Espeland, Mark

Wake Forest University Health Sciences, Winston-Salem, NC

$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 

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 
Page 32 of 103

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.

5U01 DK048489-17

Post DPP Follow-Up Study

Fowler, Sarah E.

George Washington University, Washington, DC

$650,000

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. 

5U01-DK048489-17

Sex hormones & sex hormone binding globulin effects on diabetes risk in women in DPP

Fowler, Sarah E.

George Washington University, Washington, DC

$350,000

To date neither phenotypic factors nor genetic factors that may contribute specifically to diabetes 

risk among women have been explored in the Diabetes Prevention Program (DPP). Associations 

of low estrogen status with increased diabetes risk, and associations of low concentrations of sex 

hormone binding globulin (SHBG) with increased diabetes risk, have been observed separately 
Page 33 of 103

in other studies. However, little published data connects these factors with formally ascertained 

conversions to diabetes mellitus, and prior studies have not specifically identified women at such 

high a priori risk as were selected for the DPP. Sex hormone binding globulin is a protein 

produce by the liver that binds to hormones with a steroid nucleus, with greatest affinity for sex 

steroids. This protein carries the majority of the circulating sex steroid mass in both men and 

women. The circulating concentration of SHBG is determined by a number of physiologic 

factors, in particular by the concentrations of sex hormones. In these relationships estrogen and 

testosterone act in opposite directions on SHBG concentration, with higher levels of estrogen 

resulting in reduced SHBG and higher levels of testosterone resulting in increased SHBG. 

Genetic effects on SHBG concentration are also recognized, and single nucleotide 

polymorphisms (SNPs) in the SHBG gene have recently been identified that produce changes in 

SHBG concentrations or function. The inter-relationships of menopausal status and/or sex 

hormone concentrations with diabetes risk among women at high baseline risk for diabetes are 

not well understood. Furthermore, the contributions of genetic effects on SHBG and its 

relationship with diabetes risk have not been well explored. Here they propose to evaluate 

associations of sex hormones and SHBG, plus genetic variants that affect SHBG, on diabetes risk 

in women in the DPP. They will evaluate 4 main hypotheses: (1) The relationship between 

baseline SHBG concentrations and risk of progression to prospectively ascertained diabetes 

differs between premenopausal and postmenopausal women. (2) Sex hormone levels will 

influence diabetes risk through effects on SHBG concentrations, and explain in part the effects of 

SHBG on diabetes risk in premenopausal and postmenopausal women. (3) Race/ethnicity or 

direct genetic variation in the SHBG gene will alter diabetes risk through effects on SHBG 

concentrations, independent of effects of sex hormones on SHBG. (4) The beneficial effects of 

treatment interventions in DPP are proportional to baseline SHBG and sex hormone 

concentrations, without differences in this effect across treatment groups.

DIETARY SUPPLEMENTS/CAM

1 R21 AT005377-01A1

Identification of novel phytoprogestins from hops and red clover

Burdette, Joanna E

University of Illinois at Chicago, Chicago, IL

$235,500

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 
Page 34 of 103

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. 

GENITOURINARY

1 R01 NR012011-01

Translating Unique Learning for Incontinence Prevention: The TULIP Project

Sampselle, Carolyn M.

University of Michigan, Ann Arbor, MI

$300,000

More than one in three US women suffer from the distressing, embarrassing, and often 

unreported problem of urinary incontinence (UI). A key committee of the 2008 International 

Consultation on Incontinence concluded that pelvic floor muscle training (PFMT) should be 

offered as first line therapy to all women with stress, urge, or mixed UI and that bladder training 

(BT) may be preferred to drug therapy. Conservative strategies are low risk and do not prejudice 

future treatments. They reasoned that such self-management practices should also prevent UI and 

conducted a RCT to test a prevention behavioral program. A group session presented an array of 

conservative self-management practices- PFMT, BT and the Knack Maneuver, which is a 

preemptive contraction to decrease stress UI and/or suppress urge UI. At 12-months postintervention they found a two-fold UI prevention effect. Moreover, they found high and 

sustained adherence: 82% at 3 months post intervention and 68% at 12 months. At four years 

follow-up, sustained adherence of 70% was predicted by early self-efficacy. This intervention is 

novel because it enables women to adopt and sustain efficacious bladder health practices for 

incontinence prevention, whereas to date conservative management approaches have focused on 

treatment. Based on what they now know, these practices should be part of standard well woman 
Page 35 of 103

care, but it is not realistic to expect busy clinicians to provide this information within the 

confines of a brief encounter. They have developed a 15-minute DVD that is a condensed 

version of the prevention behavioral session; it is culturally sensitive and has yielded comparable 

levels of knowledge and self-efficacy. Using two sites (Michigan and Pennsylvania), they aim to 

compare the outcomes of the group behavioral program to the DVD version by randomizing 600 

women aged 55 years and older to two arms of a comparative effectiveness trial. Follow-up will 

be at 3-months, 12-months, and 24-months post-intervention. (Aim 1). Controlling for age and 

BMI, they will test the hypotheses: HO1: There will be no difference in UI incidence 

demonstrated between groups (PRIMARY HO) HO2: There will be no difference in postintervention self-management adherence between groups HO3: There will be no difference in 

post-intervention self-efficacy to adopt strategies between groups They will conduct an 

economic analysis comparing the two-hour session with the DVD version (Aim 2). Describing 

the costs and analyzing the willingness to pay and employment data will be the primary focus of 

this study in order to create the foundation for a future cost-effectiveness analysis, should trial 

hypotheses be confirmed. At 36-months post-intervention, they will conduct interviews to learn 

which intervention elements contributed to sustainability of adherence (Aim 3). Their long-range 

objective is to provide a UI prevention intervention suitable for wide-spread translation at the 

point of well woman care (annual visit).

5 U01 DK058229-10

Urinary Incontinence Treatment Network: DCC

Tennstedt, Sharon L

New England Research Institutes, Inc., Watertown, MA

$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 
Page 36 of 103

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.

HIV

5-D43-TW-001039-12

AIDS International Training and Research Program

Adimora, Adaora A.

University of North Carolina Chapel Hill

Chapel Hill, NC

$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. 

5U01 AI035004-17

Women's Interagency HIV Study (WIHS)

Anastos, Kathryn

Montefiore Medical Center, New York, NY

$220,869
Page 37 of 103

Early in WIHS, the lower limit of detection for HIV-1 quantification was 4000 copies/ml. Some 

of these early timeponts have been requnatified with LLD of <80 cps/ml, specifically women 

who initiated HAART during visits 1-7. However, the high LLD of 4000 cps/ml (and those few 

with LLD of 400 cps/ml) for many samples continues to be problematic as WIHS has initiated 

investigations into new areas. This has been particularly true for studies of elite suppressors and 

long-term non-progressors (LTNP) and for cardiovascular studies in which quantitative total 

exposure to virus cannot be calculated. Further, it has been difficult to find controls for the elite 

suppressors and LTNPs as their true viral load is not known, nor is the viral load of the potential 

control.s Therefore, they propose here to measure quantitative HIV-1 RNA for all women-visits 

at which the viral load is undetectable at 4000 or 400 copies/ml. They propose to do this with 

Taqman, the current platform for viral load measurements in WIHS. This will allow more 

precise definitian of many categories of participants, necessary in several WIHS investigations, 

now and in the future. 

1 R21 AI082689-01A1

Development of Antimicrobial Peptides as Topical Microbicides

Buckheit, Robert Walter 

ImQuest BioSciences, Frederick, MD

$21,428

They 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, they 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. Their 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. Project Narrative: Over 25 million people have died 

since the first case of AIDS was identified in 1981, and the number of people living with HIV 

worldwide continues to expand - from 35 million in 2001 to an estimated 40 million in 2007. 

Almost 5 million people worldwide became newly infected with HIV and an estimated 3.8 

million human deaths were attributed to AIDS in 2007. They propose to identify HIV-1 and 

HSV-2 inhibitory antimicrobial peptides which are naturally produced by mammals through 

evaluation of peptides which are identified in the Antimicrobial Peptide Database developed at 

The University of Nebraska Medical Center. They intend to discover and develop inhibitors of 

HIV and other sexually transmitted infectious organisms for use as an effective topical 

microbicide product.
Page 38 of 103

5 R21 AI079772-02

Development of a Novel Semen-Activated Prodrug as an Anti-HIV Microbicide

Buckheit, Robert Walter

ImQuest BioSciences, Frederick, MD

$37,500

The S-acyl-2-mercaptobenzamide thioester (SAMT) inhibitors are low molecular weight 

compounds which target multiple steps in the HIV replication pathway, but primarily function to 

specifically inactivate cell-free HIV immediately upon exposure to the reactive compounds and 

to suppress the production of infectious HIV from virus-infected cells. These NCp7-targeted, 

virus inactivating compounds act by stripping coordinated zinc ions from the nucleocapsid (NC) 

protein in the infectious virion or maturing virus particle. In the process, the compounds 

irreversibly cross-link the nucleocapsid proteins rendering the virion noninfectious and defective. 

Thus, the NCp7 inhibitors interfere with two potential virus transmission mechanisms required 

for the infection of target cells in the vaginal environment. In the R21 phase of this proposal they

propose to develop new microbicides composed of polymeric prodrugs for delivery of the 

SAMTs. This delivery mechanism limits the tissue absorption of the SAMT until it comes in 

contact with the viral inoculum in semen by attaching it to a high molecular weight 

biocompatible polymer. They will conjugate the SAMT inhibitors to the polymer carrier through 

enzyme-cleavable linkages that will release the active drug product in the presence of specific 

enzymes in semen. This delivery approach offers several advantages in the context of 

microbicide action since (1) the NCp7 inhibitors can inactivate cell-free and cell-associated virus 

in semen, they will target the virus before it can diffuse in an infectious form to or into tissue, (2) 

they will add moieties to the polymer backbone that will increase the stability of the SAMT 

inhibitors by decreasing the pH local to the conjugated drug by the Donnan effect, and (3) since 

microbicides will be used by women repeatedly over many years, a polymeric prodrug approach 

will allow precise control over the tissue concentrations and exposure to anti-HIV compounds, 

limiting the chance to develop viral resistance and limiting toxicity. Critical to the development 

of this prodrug approach, biological evaluations will be performed to confirm the efficacy of the 

SAMTs in the presence of seminal plasma and vaginal fluids. Additionally, the enzymatic 

activation of the compound from its prodrug form will be evaluated in specially designed in vitro 

assays to mimic the events which must occur in the vagina and to quantify the kinetics of drug 

activation and virus inactivation in the presence of semen and other appropriate biological 

matrices. Finally, the biological properties of both semen and vaginal fluids on the efficiency of 

transmission of HIV to target cells will be evaluated to define the potential synergies between the 

antiviral activity of constituents of semen and the biological activity of the thioester inhibitors.

5-D43-TW-001042-12

Emory AIDS International Training and Research Program

Del Rio, Carlos

Emory University, Atlanta, GA

$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 
Page 39 of 103

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 

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.

1-R21-AI-088601-01

Targeted siRNA Delivery as An Anti-HIV Microbicide

Dykxhoorn, Derek Michael

University of Miami School of Medicine, Miami, FL

$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 

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. They 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, they 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. They 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.
Page 40 of 103

1 R21 AI088586-01

Development of a novel nanoparticle pyrimidinedione vaginal polymeric film as an

Ham, Anthony Sang Won

ImQuest BioSciences, Frederick, MD

$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. 

They 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, they 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 

and cell localization. Additionally, they 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). Their 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-D43-TW001038-12

AIDS international Training and Research Program

Harrison, Lee H.

University of Pittsburgh, Pittsburgh, PA

$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 
Page 41 of 103

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. 

1-R21-AI-082680-01A1

Phosphorothioate Oligonucleotides as Microbicides against HIV Transmission

Katsikis, Peter D

Drexel University, Philadelphia, PA

$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. They have identified novel lead 

microbicides that potently inhibit HIV and SIV infection/replication in vitro. During their 

previous submission they 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, their first 

generation OPB may be a potent microbicide against HIV that prevents infection at mucosal sites 

when topically applied. Their 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 their current 
Page 42 of 103

re-submission they present data on their next generation compound, a baseless phosphorothioate 

2' deoxyribose backbone (PDB) that has more potent HIV inhibitory activity than OPB. A 14mer 

PDB they 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, they 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. They hypothesize that PDB binds enveloped viruses and 

inhibits their infectivity by acting as a "chemical lectin". They 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 AI082738-02

Microbicide delivery system to target lymphoid organs

Labib, Mohamed E

Advanced BioDevices, LLC, Princeton, NJ

$37,500

Sexual transmission of HIV-1 involves complex processes involving exposure of the female 

genital tract to virus or infected cells and their transport to other sites, including local lymph 

nodes, where the virus replicates and establishes infection. It has been shown that Langerhans 

cells (LC) and dendritic cells (DC) capture the virus either from the vaginal surface or from top 

epithelium layers and transport it to draining and local lymph nodes, where it infects CD4+ Tcells. Intense development of topical microbicides is underway with the ultimate goal of 

decreasing the sexual transmission of HIV-1. Current efforts have been directed to inactivating 

the virus either at the surface of the vagina before entry, or in the squamous or stroma layers of 

the vaginal epithelium. Their physical transport modeling predicts that molecular drugs delivered 

as topical gels cannot reach draining or local lymph nodes. One possible way to deliver drugs to 

lymphoid sites surrounding the vagina is to use drug-loaded nanoparticles. Their preliminary 

results provide evidence indicating that nanoparticles can be delivered to local lymph nodes via 

vaginal application in a mouse model. To further develop this platform for use as a microbicide 

or prophylactic strategy, they propose the following plans for the R21/R33 application. In the 

R21 phase, they will study the delivery of quantum dots having different surface chemistry, 

including conjugation with targeting molecules, to determine the mode of their transport to 
Page 43 of 103

different lymphoid sites. In the R33 phase, they will use drug-loaded nanoparticles and verify the 

applicability of this platform to target important sites in the female genital tract. Physical models 

will be developed to understand the transport processes and to guide the development of the 

nanoparticle delivery system.

5 R21 AI079771-02

Small-molecule inhibitors of gp41-mediated fusion as HIV-1 topical microbicides

Lu, Min

Weill Medical College Of Cornell University, New York, NY

$37,500

In the continuing absence of an effective vaccine, topical microbicides offer a credible 

alternative preventive strategy to reduce sexual transmission of HIV-1. Several viral fusion and 

entry inhibitors have been shown to prevent SHIV infection of rhesus macaques by the vaginal 

and/or rectal routes and are in preclinical and early clinical development as microbicide 

candidates. HIV-1 membrane fusion is mediated by a series of large-scale structural transitions in 

the gp41 envelope glycoprotein. Evidence indicates that a transient gp41 species known as the 

prehairpin intermediate is a potential target for drugs that inhibit HIV-1 entry. The long-term 

goal of this research plan is to use modern molecular and structural methods to identify and 

develop a novel small-molecule gp41 fusion inhibitor for inclusion in a topical HIV-1 

microbicide. To achieve this, they will capitalize on specific surface features revealed by their 

recent structure determination of an autonomously folded, trimeric coiled-coil subdomain of 

gp41 that provides an atomic model for the putative prehairpin conformation, as well as smallmolecule lead compounds developed by means of an innovative structure-based drug design 

technology. They propose the following specific aim for the R21 component of this project: 1) 

To identify and optimize two series of novel small-molecule compounds that inhibit HIV-1 

membrane fusion by targeting the gp41 prehairpin intermediate. They will design and synthesize 

two sets of analogs of active triazinone and biphenyl compounds, characterize the equilibrium 

properties of interactions with the N-trimer coiled coil, and evaluate their anti-HIV-1 activity and 

mechanism of action. Bound inhibitors will be visualized by x-ray crystallography in order to 

allow refinement of binding affinity. The specific aims of the R33 phase of the project are: 2) To 

characterize the specificity, potency and toxicity of improved small-molecule compounds with 

enhanced gp41 inhibitory activity. They will conduct in vitro studies in primary cells and human 

cervicovaginal tissue explants to determine the virucidal activity of select small-molecule gp41 

inhibitory compounds against diverse primary HIV-1 isolates, and their potentially toxic or 

inflammatory effects. They will also use the rabbit vaginal irritation model to evaluate the 

irritation potential of the fusion inhibitors. 3) To assess the in vivo potency and breadth of 

activity of optimized small-molecule fusion inhibitors alone and in combination with entry 

inhibitors targeting HIV-1 gp120 (BMS-378806) and CCR5 (CMPD167) using the NOD/SCIDhu BLT mouse vaginal transmission model. They will evaluate the protection of humanized BLT 

mice from vaginal challenge with multiple HIV-1 variants by small-molecule fusion inhibitors 

alone and in synergistic combination with BMS-378806 and CMPD167. Their emphasis is to 

identify a new class of potent HIV-1 fusion inhibitors suitable for development as a component 

of a microbicide formulation.
Page 44 of 103

1 R21 AI088585-01

Plant-produced Actinohivin as a Candidate HIV Microbicide

Matoba, Nobuyuki

University of Louisville, Louisville, KY

$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, they 

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, they 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. They will utilize recombinant plant virusbased 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, they 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. Their success 

criteria in the R21 phase are: (1) establishing the bulk preparation procedure; (2) demonstrating 

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 their transition to the R33 phase, they 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, they will investigate potential 

overlap, complementation, synergy, and antagonism of anti-HIV activities between r/rdAH and 

other inhibitors toward potential microbicide combination strategies. Finally, they will perform 

extensive evaluations of r/rdAH upon vaginal application in rabbit and mouse models. They will 

thoroughly evaluate r/rdAH' vaginal toxicity, inflammatory potential, and stability. Upon 

determining the maximal tolerated dose of r/rdAH, they 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.
Page 45 of 103

1 UH2 AI083264-01

The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic (The 

Human Microbiome Project)

Ravel, Jacques

University of Maryland, Baltimore, MD

$125,000

Bacterial vaginosis (BV) is the most common vaginal disease in women, and yet its cause and 

effective treatment remain unknown. BV is associated with many adverse health outcomes, such 

as preterm delivery of low birth weight babies and increased risk for infection by HIV. This 

research will contribute valuable information on the causes of BV, help develop improved 

methods for preventing and treating BV, and may help reduce major reproductive health 

problems associated with BV. The vaginal microbiota play an important protective role in 

maintaining the health of women. Disruption of the mutualistic relationship that exists between 

bacterial communities in the vagina and their hosts can lead to bacterial vaginosis (BV), a 

condition in which lactic acid producing bacteria are supplanted by a diverse array of strictly 

anaerobic bacteria. BV has been shown to be an independent risk factor for adverse outcomes 

including preterm delivery and low infant birth weight, acquisition of sexually transmitted 

infections and HIV, and development of pelvic inflammatory disease. National surveys indicate 

the prevalence of BV among U.S. women is 29.2%, and yet, despite considerable effort, the 

etiology of BV remains unknown. Moreover, there are no broadly effective therapies for the 

treatment of BV, and reoccurrence is common. In the proposed research they will test the 

overarching hypothesis that vaginal microbial community dynamics and activities are indicators 

of risk to BV. To do this, they propose to conduct a high resolution prospective study in which 

samples collected daily from 200 reproductive-age women over two menstrual cycles are used to 

capture molecular events that take place before, during, and after the spontaneous remission of 

BV episodes. They will use modern genomic technologies to obtain the data needed to correlate 

shifts in vaginal microbial community composition and function, metabolomes, and 

epidemiological and behavioral metadata with the occurrence of BV to better define the 

syndrome itself and identify patterns that are predictive of BV. The five specific aims of the 

research are: (1) Evaluate the association between the dynamics of vaginal microbial 

communities and risk to BV by characterizing the community composition of vaginal specimens 

archived from a vaginal douching cessation study in which 39 women self-collected vaginal 

swabs twice-weekly for 16 weeks; (2) Enroll 200 women in a prospective study in which selfcollected vaginal swab samples and secretions are collected daily along with data on the 

occurrence of BV, vaginal pH, and information on time varying habits and practices; (3) 

Determine the gene content (metagenome) of vaginal microbial communities to assess the 

metabolic potential of representative vaginal communities in women before, during, and after the 

spontaneous remission of BV; (4) Characterize suites of expressed genes (metatranscriptome) in 

communities representative of vaginal community types in healthy women, as well as before, 

during, and after the spontaneous remission of BV; and (5) Apply model-based statistical 

clustering and classification approaches to associate the microbial community composition and 

function, with metadata and clinical diagnoses of BV. The large body of information generated 

will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and 

drive the development of better diagnostic tools for BV. Furthermore, the information will 

enable a more personalized and effective treatment of BV and ultimately, prevent adverse 

sequelae associated with this highly prevalent disruption of the vaginal microbiome. 
Page 46 of 103

1 R21 AI088597-01

Engineering antiviral innate immunity for safe and effective microbicides

Shen, Hong

University of Washington, Seattle, WA

$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. They 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 

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, they 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.

1 R21 AI088595-01

Exploring the Role of Vif Antagonists in Preventing Sexual HIV Transmission

Stevenson, Mario

University of Massachusetts Medical School, Worcester, MA

$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, they focus on a 

novel mechanism that has not previously been explored for HIV prevention. In 2002, it was 
Page 47 of 103

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. They 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. Their 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.

5 D43 TW001035-12

Vanderbilt University-Cidrz AIDS International Training and Research Program

Vermund, Sten H

Vanderbilt University, Nashville, TN

$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 
Page 48 of 103

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. 

5 R21 AI082701-02

Gp340 and syndecan inhibition based microbicide for HIV

Weissman, Drew

University of Pennsylvania, Philadelphia, PA

$37,500

Education and microbicides active against HIV represent the best approaches to controlling the 

epidemic worldwide in the absence of a protective vaccine. Their research program studies the 

earliest events in genital tract transmission. They have identified a protein expressed by genital 

tract epithelial cells that could serve as a potential target for inhibition of transmission of HIV 

called gp-340. They have demonstrated that gp-340 is expressed on the cell surface of vaginal 

and cervical epithelial cells, in vivo, in vitro, and ex vivo and binds HIV envelope. Of 

significance to genital tract transmission, gp-340 binding of virus leads to an increase in both the 

infectivity and half-life of the virus. Gp-340 expressed by genital tract tissue and cell lines also 

mediates transcytosis of HIV, the vesicular transport of macromolecules from one side of a cell 

to the other. A second molecule called syndecan has been studied and shown to have similar 

trans-infection and transcytosis properties and is also expressed by genital tract cells. They have 

identified a peptide inhibitor of envelope binding to gp-340 that blocks both gp-340 mediated 

trans-infection and transcytosis in in vitro and ex vivo models of genital tract transmission. This 

peptide contains a portion of a motif that inhibits syndecan mediated transinfection, as well, and 

they will modify this peptide to inhibit envelope binding to both macaque gp340 and syndecan 

and develop it into a microbicide. This potential role of gp-340 and syndecan to act at a stage of 

infection after delivery to the lumen of the genital tract but prior to interaction with and infection 

of target cells is very attractive and novel in microbicide design. They hypothesize that 

interfering with this process will inhibit or block genital tract transmission. In the initial R21 

portion of this proposal, they will establish in vitro macaque systems of genital tract 

transmission. If they demonstrate that macaque gp340 and syndecan mediate trans- infection and 

transcytosis and V3 loop derived peptides or improved versions block macaque gp340 and 

syndecan mediated transinfection and transcytosis, they will proceed with the R33 portion of the

grant. The specific aims of this are: microbicide development with in vitro testing and to test the 

effect of blocking gp340 and syndecan-HIV Env interaction on genital tract SIV transmission in 

the rhesus macaque vaginal transmission model. Through these specific aims, they will develop a 

new type of microbicide and determine the role of genital tract gp-340 and syndecan in HIV 

transmission. If successful, these studies will deliver a new microbicide based on host cell 

interactions with HIV that promote genital tract transmission to preclinical trial studies.
Page 49 of 103

5 U01 AI034994-17

Washington Metropolitan Women's Interagency HIV Study

Young, Mary A.

George Washington University

Washington, DC

$100,000

The Washington Metropolitan WINS (WMW) Consortium has enrolled and retained a 

representative cohort of HIV infected and HIV uninfected women since 1993 with the purpose of 

investigating the consequences of HIV infection and its treatment. Although significant progress 

has been made in both their understanding and treatment of HIV, curative therapy is still not 

available and the chronically administered complex therapies used to treat HIV are not always 

successful. Treatment with highly active antiretrovirals (HAART) appears to be associated with 

a wide range of adverse effects and the impact of other co-pathogens such as HPV and HCV has 

yet to be fully elucidated. Additionally, the early cohort of infected women is aging, and the 

effects of age and changes in sex steroids both on the long term outcomes of HIV, on

neurocognition and the effects of HAART treatment needs investigation. The WMW has joined 

with centers around the country and with sites across the metropolitan Washington region to 

develop a scientific plan to address these issues. A successful and flexible infrastructure has been 

established to allow us to accomplish these scientific aims and to assure ongoing retention of this 

important cohort. The WMW has successfully participated in all elements of the WIHS protocol, 

and has actively supported the infrastructure of the national WIHS. WMW investigators have 

participated in all of the major WIHS scientific initiatives. Additionally, the WMW has 

established both a local specimen repository and contributes to the national specimen repository. 

As the study has matured, an increasing number of collaborations have been established with 

local investigators to allow for broader access to the rich repository of WIHS specimens. Further, 

the WMW has expanded its local epidemiologic expertise to allow for on site data analyses. This 

application will describe both their accomplishments to date and the structure that they have 

established to 1) advance the scientific agenda as outlined in Part A, 2) to continue to expand

their local collaboration in order to better define the status of women with HIV, and 3) to bring 

to fruition the promises of a sustainable treatment of this devastating disease.

IMMUNITY/AUTOIMMUNITY

5R21HL093181-02

Role Of 15-Lipoxygenase In Enhanced Pulmonary Vasoconstriction In Females

Pfister, Sandra L

Medical College Of Wisconsin

$190,000

While relatively rare, idiopathic pulmonary arterial hypertension is a medically significant 

disease that occurs more frequently in young women. The disease is usually catastrophic for 

those afflicted. Identifying endogenous pulmonary factors that may predispose females to the 

development of pulmonary hypertension is timely and important considering the abundance of 

clinical data indicating sex differences in vascular disease. Furthermore, this work is intended to 

advance new concepts in women's health research and the study of sex/gender differences. 

Pulmonary arterial hypertension encompasses a group of diseases characterized by high 
Page 50 of 103

pulmonary artery pressure and pulmonary vascular resistance. Vasoconstriction, vascular 

remodeling and thrombosis all contribute to the increased vascular resistance. Central to the 

proposed studies is that while relatively rare, idiopathic pulmonary arterial hypertension is a 

medically significant disease that occurs more frequently in young women. The disease is 

usually catastrophic for those afflicted. Mechanisms to explain the sex- difference in pulmonary 

arterial hypertension have not been well studied. The main focus of the current proposal is to use 

a rabbit model to explore the role of sex in a novel signaling pathway that regulates pulmonary 

vascular tone. Results will lay the fundamental conceptual groundwork for future studies to 

understand more completely the pathogenesis of pulmonary hypertension in women. 

Furthermore, this work is intended to advance new concepts in women's health research and the 

study of sex/gender differences. Specifically, their research provided the first evidence that in 

pulmonary arteries obtained from female rabbits, endothelium-dependent contractions to both 

arachidonic acid and methacholine were enhanced when compared to responses in males. 

Pharmacological studies with inhibitors of arachidonic acid metabolism indicated that the factor 

was a lipoxygenase metabolite. They also present the first data that lipoxygenase metabolites are 

increased in females compared to males and the protein expression of 15-lipoxygenase is greater 

in female pulmonary arteries. While sex differences in vascular responses to various vasoactive 

agents have been documented, no studies have investigated the role of sex differences on 

lipoxygenase metabolism of AA in pulmonary arteries. This proposal is designed to explore the 

specific hypothesis that differences in AA metabolism by 15-LO contribute to the increased 

endothelium-dependent pulmonary vasoconstriction in females compared to males. To further 

develop this novel hypothesis, studies will be performed in pulmonary artery vascular 

preparations using chemical, biochemical, physiological and pharmacological approaches. Two 

specific aims will be explored: 1) To chemically identify and biologically characterize the 

vasoconstrictor 15- lipoxygenase metabolite(s) produced by the rabbit pulmonary artery 

endothelium and 2) To examine the cellular mechanisms contributing to enhanced 15-

lipoxygenase expression in females compared to males. These proposed studies will not only 

provide new insights into the role of endogenous arachidonic acid-derived factors in the 

pathogenesis of pulmonary arterial hypertension but will also advance their knowledge in 

women's health research by identifying possible mechanisms that contribute to sex-related 

differences in the incidence of pulmonary arterial hypertension.

5R21AI083894-02

Role of Sex Differences In The Expression & Function Of Regulatory T Cells In Sle

Singh, Ram Pyare

University Of California Los Angeles

$231,000

They propose to study regulatory T cells (CD4 and CD8) (comparing male to female SLE 

patients and male to female healthy individuals) for quantities, suppressive capacities and 

differences in gene expression. The ability of sex hormones to change Treg numbers, functions, 

and gene expression will be studied. Regulatory CD4+T cells and CD8+T cells have important 

roles in suppressing autoimmune disease in the peripheral immune system. Impaired function of 

regulatory/suppressor T cells contributes to development of autoimmunity. The goal of this 

project will be studying the quantities and functions of T regulatory cells in healthy controls and 

patients with SLE, comparing males to females in both groups (given the fact that lupus disease 

is much more frequent in females than in males). The first aim is to quantify, immunophenotype, 
Page 51 of 103

and perform functional analysis of the Treg cell subsets in healthy controls, and in male lupus vs 

female lupus. The second aim is to compare gene expression profiles of CD4+CD25+hiTreg and 

CD8+Ts cells in male vs female lupus patients and to compare them with healthy controls. 

Finally, they will test the effect of testosterone and estradiol in these cells in vitro to see their 

effects on cell phenotypes, gene expression, signaling and regulatory functions. The overall 

purpose is to understand the molecular network of these CD4+T regulatory cells and CD8+ 

suppressor cells in systemic autoimmunity.

5 R01 TW008151-02

Molecular Epidemiology of Drug Resistance and Population Genetic Structure of Pla

Lu, Fangli

Sun Yat-Sen University, Guangzhou, China

$50,000

This project will be of significant benefit to public health programs aimed at identifying and 

combating drug-resistant malaria, and has 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 

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, their 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 they 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 
Page 52 of 103

structure and specific epidemiological characteristics of P. vivax transmission in Yunnan and 

Hainan, China. 

1 R21 AR058010-01A1

Mechanisms if IL-35 Protection Against Arthritis

Pascual, David W., Ph.D.

Montana State University, Bozeman, MT

$200,000

The project will evaluate the therapeutic potential of IL-35 to treat rheumatoid arthritis (RA). 

RA, a chronic inflammatory disease of the joints, manifests as a chronic synovitis and 

progressive destruction of the joints, leukocyte infiltrates, and cartilage destruction and bone 

erosion. It is believed this destruction is supported and perpetuated by proinflammatory 

cytokines contributed by autoreactive T cells. Rodent models have been developed that mimic 

arthritis, and one such model, collagen-induced arthritis (CIA), requires immunization with 

heterologous collagen II. Oral tolerance and treatments with regulatory cytokines have been 

suggested as possible interventions to treat arthritis. One such new therapeutic is the regulatory 

cytokine, IL-35; however, its mode of action has yet to be determined. IL-35 is a heterodimer 

cytokine composed of IL-12p35 plus IL-27 EBI3 subunits. They recently expressed IL-35 as a 

single polypeptide using eukaryotic expression systems. The recombinant mouse IL-35 has the 

expected molecular weight, and it is recognized with antibodies to IL-12p35 and IL-27-EBI3. 

Functional analysis reveals that IL-35 can completely block development of clinical symptoms 

of CIA. This disease suppression does appear to be IL-10-dependent, produced by heterogeneous 

regulatory T cell subsets, including CD25+ CD4+ T cells, as well as CD39+ CD4+ T cells. Thus, 

additional studies are warranted to investigate the nature of these regulatory T cells and learn 

which mononuclear cells are responsive to IL-35's action. Given these findings, the hypothesis to 

be tested in this application is that IL-35 intervention will reduce disease severity and limit 

disease progression of CIA by the stimulation of regulatory T cells. To test this hypothesis, two 

Specific Aims are proposed. Studies in Specific Aim 1 will determine if IL-35 in a 

paracrine/autocrine fashion stimulates endogenous IL-35 production for treatment of CIA and 

determine the cell types involved to facilitate IL-35's action. Studies in Specific Aim 2 will 

define the regulatory T cell subset induced by IL-35 that is responsible for protection against 

CIA and determine which inflammatory T cell subset is diminished. These collective studies will 

provide the foundation of whether IL-35 can be considered in RA intervention strategies and 

whether alternative regulatory T cells can be defined that would facilitate IL-35's therapeutic 

impact in humans.

2 R01 CA102667-06A1

Effects of Malaria on EBV Persistence in Children

Rochford, Rosemary, Ph.D.

Upstate Medical University, Syracuse, NY

$167,750

Endemic Burkitt's lymphoma (BL), the most prevalent childhood cancer in Equatorial Africa, is 

a rapidly growing B-cell malignancy that is ultimately fatal if untreated. The knowledge gained 

by this study will improve the understanding of the etiology of endemic BL which will 

ultimately allow for the design of programs aimed at the prevention of BL. While there is a 

consensus that infection with Epstein-Barr virus (EBV) and repeated infections with Plasmodium 
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falciparum malaria in childhood (e.g. holoendemic malaria) are essential components in the 

etiology of BL, the mechanisms of malaria and EBV interactions that increase the risk for 

endemic BL remain to be elucidated. The long-term goal of this research is to identify the events 

that initiate B cell oncogenesis in BL. The overall objective of this proposal is to continue this 

investigations of EBV and malaria interactions in Kenyan infants at risk for endemic BL. In this 

current R01 (CA102667), they followed a prospective cohort of children with divergent malaria 

exposures from 2 months through 36 months of age. They observed that children born in the 

malaria holoendemic region had a significantly earlier age of primary infection with EBV, with 

~35% infected by 6 months of age. Importantly, children infected early in life maintained a 

chronic viral load. These studies support the long-held hypothesis that early age of EBV 

infection is a risk factor for BL. What they do not know however, is why these infants are 

infected early in life and how early age of infection limits control of EBV. Based on this data and 

the data of others, they propose a model whereby susceptibility of infants to infection with EBV 

by 6 months of age is linked to placental malaria. Infants infected early in life while they have 

under-developed immune responses will have poor immunologic control of the virus. The long 

term consequences of poor immunologic control is a greater number of latently infected cells 

which can ultimately exhaust the immune response against EBV and increase the risk for a 

malignant clone to emerge from the latently infected B cell. This central hypothesis is that 

placental malaria alters an infants ability to control primary EBV infection resulting in infection 

earlier in life and failure to develop effective EBV immunity. They will establish an infant cohort 

by enrolling pregnant women attending an antenatal clinic at Chulaimbo Hospital in Kisumu 

District, Kenya where malaria is holoendemic, and follow infants prospectively from birth to 

their second birthday. To test this hypothesis, they determine the effects of placental malaria on 

transfer of maternal EBV-specific neutralizing antibodies and in utero sensitization to EBV 

antigens; determine the factors influencing susceptibility of infants to EBV by 6 months of age; 

determine the effects of early age of EBV infection on the development of EBV-specific immune 

responses, the frequency of atypical exhausted memory B cells, and the emergence of premalignant B cells. If this model proves valid, the implications are that prevention of BL should 

focus on delaying the age of EBV infection by focusing on pregnant women with placental 

malaria, or on blocking transmission to infants.

1 R21 AG034523-01A1

Exploring factors influencing gender disparities in access to transplantation

Segev, Dorry

Johns Hopkins University, Baltimore, MD

$246,000

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 
Page 54 of 103

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 AI090344-01

Sex Differences in Protective Immunity Against Influenza A Viruses

Klein, Sabra

Johns Hopkins University, Baltimore, MD

$205,000

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 
Page 55 of 103

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. 

MENOPAUSE

5 R01 AG027702-05

Estrogen: Neuroprotection in the Perimenopause

Etgen, Anne M.

Yeshiva University, Bronx, NY

$50,000

Alterations in the hypothalamic-pituitary-ovarian axis in perimenopausal women are associated 

with multi- organ risk factors for disease, yet the biological mechanisms underlying this 

increased disease risk are largely unknown. This proposal addresses unanswered questions 

regarding the vulnerability of the middle- aged brain to global ischemia. In young female rats, 

the presence of physiological levels of estradiol before and after global ischemia, as might occur 

during cardiac arrest, reduces hippocampal CA1 neuron loss and associated cognitive 

impairments. Whether estradiol retains its neuroprotective actions in middle-aged females, and 

whether the age-related decline in insulin-like growth factor-l (IGF-I) increases vulnerability to 

ischemia-induced neurodegeneration and cognitive impairment, are unknown. This proposal 

aims examines the roles of age, estrogen and IGF-I in the survival and function of hippocampal 

neurons in a rat model of global ischemia. The underlying hypotheses are (1) that the middleaged brain retains its responsiveness to the neuroprotective actions of estradiol if the duration of 

estrogen withdrawal is brief ("critical period hypothesis") or circulating levels of IGF-I are 

maintained, and (2) that estrogen acts in the middle-aged brain to activate specific cell survival 

pathways and thereby intervenes in apoptotic cascades to prevent death of neurons otherwise 

"destined to die". Specific Aim 1 uses stereological cell counting and behavioral tests to evaluate 

the outcome of global ischemia in middle-aged female rats that are intact, ovariectomized at 

various intervals prior to insult, or ovariectomized and treated with estradiol at various intervals 

after ovariectomy. If estradiol does not preserve neurons and cognitive function in older

hormone-deprived animals, we, will also determine if IGF-I can reinstate estrogen protection. 

Specific Aim 2 examines the apoptotic death cascades triggered by global ischemia and 

identifies the site at which estrogen intervenes in these cascades. They will examine 1) mitogenactivated protein kinase and cAMP response element binding protein at early times after 

ischemia; 2) the anti-apoptotic gene Bcl-2 and activation of caspase 3 at later times after 
Page 56 of 103

ischemia; 3) inactivation of Akt and subsequent activation of the forkhead transcription factor 

FKHRL1 at early times after ischemia. These experiments will provide new information on the 

potential for hormone therapy instituted during the perimenopausal transition to protect the brain 

from damage due to global ischemia.

5 U01 AG012531-17

SWAN: Study of Women's Health Across The Nation

Finkelstein, Joel S

Massachusetts General Hospital, Boston, MA

$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 

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 
Page 57 of 103

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.

1 R21 AG037832-01

Ovarian hormone-independent sex chromosome effects in menopause

Ji, Hong

Georgetown University, Washington, DC

$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 

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). 
Page 58 of 103

1 R21 NS066147-01A1

Effects of estrogen on brain morphology and neuronal integrity in early menopause

Kantarci, Kejal

Mayo Clinic, Rochester, MN

$213,812

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 

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. 

U01 AG032699-03

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, Seattle, WA

$132,000
Page 59 of 103

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), 

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 R01 AG027713-05

Menopause: Decreased Response to Increasing Inflammation

Maggi, Adriana Caterina

University of Milan, Milan, Italy

$50,000

The long-term goal of their research is to find treatments for the prevention of the disorders 

associated with menopause which are safer and more efficacious than present hormone 

replacement therapy (HRT). The failure of present HRT to fulfill medical and women's needs has 

to be ascribed to an insufficient knowledge of the biology of menopause. The aim of their 

research is focused on the understanding the consequences of cessation of ovarian functions on 

the physiology of non-reproductive organs such as bone, brain, arteries and fat. In particular their 

studies and the studies proposed in the present project will focus on the effects of estrogen 

decreased production at menopause transition and after in non-reproductive organs. Given recent 

results demonstrating that in non-reproductive organs of fertile female mice estrogen receptors 

(ERs) are activated by factors other than estrogens, their Specific Aim #1 will focus on assessing 

the extent to which ERs are transcriptionally active during menopause transition and after. They 

will then try to identify the factor(s) involved in ER activation. This part of the project relates to 

questions which so far could be addressed only partially with the current technology. The 

generation of a novel model of reporter system, the ERE-Luc mouse, will enable us to precisely 

quantify ER activity in the organs of interest and facilitate the search of factors involved in ER 
Page 60 of 103

unliganded activation. Specific Aim #2 will give us the opportunity to test an original hypothesis 

that would explain the widespread protective effects provided by the estrogen-ER system. This 

hypothesis is based on numerous very recent observations made in ours and several other groups 

showing that estrogens and cognate receptors may exert a strong anti-inflammatory action by 

inhibiting the immune response of cells of the monocyte lineage. They here propose that 

menopause consists in a decreased response to increased inflammation. They will test this 

hypothesis by the direct assessment of ER relevance on macrophage activity through the 

generation of a novel conditional ERalpha K.O. mouse. Furthermore, using brain as a 

paradigmatic non-reproductive organ, they will measure basal and induced activity of brain 

inflammatory cells. Finally, the specific involvement of ER anti-inflammatory activity in the 

development of menopause-associated diseases will be tested with the study of the activity in 

menopause of another class of intracellular receptors devoted to the control of inflammation, the 

PPARs.

5 R01 AG027697-05

Effects of Chronic Estrogen on TIDA Neurons: Role of Cytokines and NO

Mohankumar, Puliyur S.

Michigan State University, East Lansing, MI

$50,000

Perimenopause is one of the most complex and least understood states of a woman's life. Many 

of the health risks associated with this state were believed to be due to decreases in estrogen 

levels and that estrogen could protect against health risks faced by perimenopausal women. 

However, estrogen fluctuates during perimenopause and if at all increases during the 

premenstrual and follicular phases. Recent clinical trials have shown that chronic administration 

of estrogenic compounds in postmenopausal women may increase the risk for several diseases. 

Therefore, it is important to investigate the effects of estrogen exposure on various organ 

systems. Studies so far indicate that estrogen's effects in the brain are beneficial. These reported 

effects, however, deal with non-hypothalamic regions of the brain. The effects of chronic 

estrogen exposure on the hypothalamus which regulates several key body functions have not 

been investigated. This is critical because women use estrogenic preparations on a prolonged 

basis and are exposed to endogenous estrogen throughout their adulthood. This proposal focuses 

on the effects of chronic estrogen exposure on one of the estrogen sensitive neuronal systems of 

the hypothalamus, namely, the tuberoinfundibular dopaminergic (TIDA) system. Dopamine 

(DA) released from TIDA neurons inhibits prolactin (PRL) secretion from the anterior pituitary. 

Age-related reductions in TIDA activity is associated with hyperprolactinemia and appearance of 

mammary and pitutiary tumors in animal models. The mechanisms behind the loss of TIDA 

neuronal function is not clear. In this application, they are proposing a novel hypothesis and an 

interesting model to study how estrogen could affect TIDA neurons and increase PRL levels. 

This series of studies is important because women not only use estrogen on a long-term basis in 

HRT but are also exposed to environmental estrogens. Prolonged exposure to estrogen and 

elevated levels of PRL may promote the risk for breast cancer.

5 R01 AG027678-05

Biological Mechanisms of Arterial Stiffening with Age and Estrogen Deficiency

Moreau, Kerrie

University of Colorado, Denver, CO
Page 61 of 103

$47,579

The purpose of this R01 proposal is to determine the key functional mechanisms by which the 

loss of female sex hormones, particularly estradiol (E2), contribute to the age-related decrease in 

large artery compliance. The overall hypothesis is that basal large artery compliance will 

decrease in response to acute sex hormone suppression in pre- and perimenopausal women due 

in part to a decrease in vascular endothelial-dependent vasodilatory tone mediated, in part, to the 

development of vascular oxidative stress. However, E2 administration during sex hormone 

suppression will decrease vascular oxidative stress, improve endothelial vasodilatory tone and 

restore arterial compliance to basal levels. Secondary and tertiary hypotheses are that the changes 

in arterial compliance and vasodilatory function with sex hormone suppression and E2 will be 

related to unfavorable, and favorable, respectively, changes in vascular endothelial cell protein 

expression including oxidant (e.g., NADPH) and antioxidant (e.g., glutathione peroxidase) 

enzymes, vasoconstrictors (endothelin- 1), and estrogen receptor alpha (ERalpha). To test these 

hypotheses, healthy pre-, peri-, and postmenopausal women will be studied at before and 

following acute sex hormone suppression (gonadotropin releasing hormone antagonist 

[GnRHant]) with or without E2 add-back therapy. The GnRHant intervention will enable us to 

study the direct mechanisms associated with sex hormone deficiency and the E2 add-back 

intervention will enable us to isolate the independent effects of E2. Insight into the molecular 

mechanisms mediating the decrease in large artery compliance will be obtained using a novel 

translational research technique to determine changes in vascular endothelial cell protein 

expression of genes involved in the regulation of cellular and systemic adaptations to aging and 

sex hormone deficiency including oxidative stress, nitric oxide bioavailability, and the potent 

transcription factor ERalpha proteins. The results should provide new insight into the integrative 

biological mechanisms by which sex hormone deficiency modulates the age-related reduction in 

large artery compliance in women as they transition through the menopause.

2 U01 AG017719-11A2

SWAN Repository III

Sowers, Maryfran

Universtiy of Michigan, Ann Arbor, 

$100,000

This competing renewal application is to provide for ontinued 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 their 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 
Page 62 of 103

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.

5 U01 AG012553-16

Study of Women’s Health Across the Nation III

Tyrrell, Kim Sutton

University of Pittsburgh, Pittsburgh, PA

$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. 

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. 

1 R21 NR012218-01

Menopause Symptom Clusters: Refocusing Therapeutics

Woods, Nancy Fugate, Ph.D.

University of Washington, Seattle, WA

$200,000
Page 63 of 103

The results of this study will help clinicians and women, themselves, identify symptoms that 

cluster together and that may have different causes. Knowing which cluster of symptoms a 

woman has may help her clinician recommend the treatment or treatments that are most likely to 

work best for her. Using some of the genetic and hormone tests, as well as information about the 

woman's history, such as stressful experiences she has had, may help understand what causes 

some of her symptoms and may help her and her clinician decide on the best treatment available 

for her. Although women experience clusters of symptoms during the menopausal transition, 

most research focuses on individual symptoms such as hot flashes. The proposed study shifts the 

paradigm from focusing on individual symptoms to symptom clusters (SCs). Re-analyzing data 

on symptoms and genetic polymorphisms, endocrine biomarkers, symptom vulnerability factors 

and sociobehavioral risk factors from over 500 participants in the Seattle Midlife Women's 

Health Study (P50 NR02323, R01 NR04141, P30 NR04001, P30 ES07033) with longitudinal 

follow-up spanning up to 19 years will allow us to achieve these aims: 1) identify prevalent 

symptom clusters during the late reproductive stage, early and late menopausal transition stages, 

and early postmenopause using latent class analysis; 2) determine the consistency of symptom 

clusters as women change from one menopausal transition stage to the next; 3) test models 

linking genetic polymorphisms, endocrine biomarkers, symptom vulnerability factors, socialbehavioral risk factors and menopause-related factors to symptom clusters, and outcomes of 

well-being and symptom interference; 4) conduct a systematic review of controlled clinical trials 

to identify symptoms as secondary treatment effects and adverse effects that will inform us about 

therapies for symptom clusters and 5) synthesize results of the empirical analyses and systematic 

review to develop novel symptom cluster management protocols to be tested in future feasibility 

studies. An interdisciplinary scientific advisory board including National Institute on Agingfunded MS-FLASH clinical trials investigators will provide their research team an opportunity 

for immediate sharing of their results in order to inform design of symptom cluster management 

approaches as well as their ongoing studies, including the generation of ancillary studies of 

symptom clusters and related mechanisms.

MENTAL HEALTH

5R21HD058989-02

Novel Approaches To Understanding Mental Disorder, Substance Abuse And Hiv-Risk A

Whitbeck, Leslie B

University Of Nebraska Lincoln

$255,535

This R21 developmental application will set the stage for the first multi-state longitudinal 

diagnostic study of homeless women. It builds on more than a decade of work with hard to 

access homeless populations and a prior three-year longitudinal diagnostic study of homeless 

adolescents. This application will fund the development of innovative measures and sampling 

techniques specifically for this understudied population and for the piloting of measures with a 

sample of 200 homeless women in two Midwestern cities. This [revised] R21 application seeks 

two years of support to develop state-of-the-science methodologies to address four important 

gaps in existing research with homeless women: 1) capture the diversity of circumstances among 

a fluid and hard-to-access population; 2) increase their understanding of mental and substance 

use disorders (particularly personality disorders) across the diversity of homeless women; 3) 
Page 64 of 103

improve their understanding trajectories to homelessness through development of an innovative 

event history calendar approach; and 4) advance knowledge of homeless women's health and 

HIV-risk by circumstance and trajectories to homelessness. This research will provide 

measurement development and preliminary studies for a multi-state longitudinal R01 designed to 

advance their understanding of mental and substance use disorders among homeless women, 

their movement into and out of homelessness, the consequences of homelessness for women and 

minor children in their custody, and women's health, HIV-risk, and HIV testing behaviors. The 

planned longitudinal research will focus on a growing but poorly understood population of the 

nation's most vulnerable women. The specific aims of this R21 developmental application are to 

1) develop and pilot a sampling plan that will better reflect the diversity of homeless women; 2) 

develop and pilot an innovative events history calendar for use with homeless women; 3) 

program and pilot Axis 1 (UM-CIDI) and Axis II (DIPD-IV) diagnostic interview schedules for 

computer-assisted personal interviews with homeless women; 4) develop and program women's 

health and HIV-risk measures; and 5) pilot the measures with 200 homeless women in two 

Midwestern cities.

5R21DA025543-02

Race And Hiv-Risk: Contextual And Neurocognitive Influences On Sex Partnerships

Floyd, Leah

Johns Hopkins University

$246,574

Currently, there is a hidden HIV epidemic among young adult African American females with no 

history of substance abuse. These women are at increased risk for contracting HIV by virtue of 

their social/sexual networks. If successful, the proposed research project: (1) should provide 

insight into why African American females have higher rates of HIV than their white 

counterparts; (2) highlight the importance of considering the contextual influences of drugs, that 

is how drug markets change social structures and altered sexual norms and behaviors of entire 

communities; and (3) increase understanding of the processes through which neighborhood 

factors influence HIV risk. The primary aim of this R21 application in response to NIDA's 

ANSWHR Initiative (PAS-07-381) is to address gaps in literature focused on HIV risk and 

disparities among females. In the United States as rates have increased among females, the rate 

of HIV/AIDS diagnoses for African American females approaches 25 times the rate for white 

females. Despite the broad base of findings documenting health disparities in HIV, extant studies 

cannot explain why African Americans continue to be disproportionately affected. Currently, 

there is a hidden HIV epidemic among young adult African American females with no history of 

substance abuse. These women are at increased risk for contracting HIV by virtue of their social 

networks. The proposed study requests two years of support for a cross sectional epidemiologic 

examination of racial/ethnic differences in sexual partnerships among 220 females (110 Black 

and 110 White) residing in low socioeconomic status (SES) neighborhoods. Guided by ecosocial 

theory, they seek to explain why these differences exist across race/ethnicity. They will consider 

the extent to which neighborhood social and economic factors (e.g., drug markets) interact with 

race/ethnicity to produce different levels of HIV risk. They will expand drug abuse and HIV 

prevention research by, in addition to considering individual differences, examining the 

influences of neighborhood drug markets on the sexual behaviors, sexual partnerships and rates 

of a sexually transmitted disease among young adult females residing in disadvantaged 

neighborhoods. Finally, the proposed study will move beyond descriptive social epidemiology 
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and into identifying neurocognitive processes that mediate/moderate relationships between 

neighborhood factors and individual behavior. As, a small yet growing base of research suggests, 

to the extent that individuals are able to make decisions, solve problems and control impulses, 

neurocognitive functions may serve as protective factors or pathways through which external 

social factors influence individual behavior. Identifying social factors that influence partner 

selection and individual level factors that may serve to reduce the adverse effects of living in 

disadvantage neighborhoods will inform HIV prevention interventions for African American and 

underserved women. If successful, the proposed research project: (1) should provide insight into 

why African American females have higher rates of HIV than their white counterparts; (2) 

highlight the importance of considering the contextual influences of drugs, that is the influence 

of drug markets on social structures and sexual norms and behaviors; and (3) identify modifiable 

individual level factors linking neighborhood social and economic factors to individual HIV risk 

behaviors.

5 DP1 OD003312-04

Emotions are Emergent Events Constrained by Affective and Conceptual Processes

Barrett, Lisa

Northeastern University, Boston, MA

$391,250

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.
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MUSCULOSKELETAL SYSTEMS

1 R21 AR056404-01A2

A link between parity, trunk muscle function, and degenerative spondylolisthesis

Cholewicki, Jacek

Michigan State University, East Lansing, MI

$199,929

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. 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. They 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. 

-----------
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The Osteoarthritis Initiative

$650,000

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.

ORWH supported Clinical Centers in the Osteoarthritis Initiative: 

N01 AR22262-12-0-1

Clinical Centers For The Osteoarthritis Initiative - Rhode Island

Eaton, Charles B.

Memorial Hospital of Rhode Island, Pawtucket, RI

N01AR22259-12-0-1

Clinical Centers For The Osteoarthritis Initiative

Hochberg, Marc

University of Maryland Baltimore, Baltimore, MD

N01 AR22261-13-0-1

Clinical Centers For The Osteoarthritis Initiative

Jackson, Rebecca

Ohio State University, Columbus, OH

N01 AR22260-13-0-1

Clinical Centers For The Osteoarthritis Initiative

Kwoh, Kent

University of Pittsburgh, Pittsburgh, PA

---------------------------
Page 68 of 103

1 R21 HL093068-01A2

Sexual Dimorphism of Skeletal Muscle

Huxley, Virginia H

University of Missouri-Columbia, Columbia, MO

$209,109

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 

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 
Page 69 of 103

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 R01 AR057139-01A2

Structural, Molecular, and Functional Specialization in Osteocyte Mechanosening

Weinbaum, Sheldon, Ph.D.

City College of New York, New York, NY

$200,000

Osteocytes are the cells in bone that sense mechanical loading and translate mechanical strain 

into biochemical signals that initiate modeling and remodeling through which bone adapts its 

structure to its mechanical loading environment. This ability is key to skeletal health; failure to 

adapt results in bone in fragility. Increases and decreases in osteocyte mechanosensitivity have 

been implicated in regulating the bone response to anabolic agents, and conversely the bone loss 

resulting from estrogen loss, respectively. Thus understanding how osteocytes "perceive" and 

transduce mechanical signals may provide key new insights into bone physiology leading to the 

identification of novel therapeutic targets against bone loss due to aging and disease. Osteocytes, 

the cells that reside within bone matrix, are the most abundant bone cells. They function as the 

mechanical sensors in bone, and are critical to activation and coordination of osteoclastic and 

osteoblastic activities by which bone adapts to mechanical usage, maintains its health and 

prevents fractures. The mechanisms underlying osteocyte mechanotransduction are not well 

understood, though changes osteocyte mechanosensitivity have been implicated in regulating the 

effect of both bone anabolic agents and sex hormones. The investigators have developed 

engineering models which show that small whole bone strains can be amplified locally around 

osteocyte processes by focal attachments to the canalicular wall. Osteocyte cell bodies cannot see 

similar high strains as they are too compliant and lack the cellular attachments needed for local 

strain amplification. These mathematical models argue that the osteocyte cell process may be 

uniquely designed to function as a detector of small tissue strains. To test this hypothesis, they 

developed a broad-based multiple-PI program that combines expertise in ion channel physiology, 

in vivo osteocyte structure/biomechanics and bioengineering/modeling to understand how 

osteocytes perceive and transduce their local mechanical environment. This program will a) 

examine the functional polarity of osteocyte mechano- responsiveness using electrophysiological 

approaches on cultured osteocytes (Aim 1), b) identify the molecular components of 

mechanotransduction complexes in osteocytes (Aim 2), c) characterize the structure of the 

mechanotransduction complex in osteocytes in vivo (Aim 3) and d) build integrative 

mathematical models relating local hydrodynamic forces and membrane strains at osteocyte 

processes and cell bodies to cellular responses in vitro and in vivo (Aim 4). They have also 

developed a novel technology ("Stokesian" Fluid Stimulus probe) that allows us to 

hydrodynamically load osteocyte processes vs. cell bodies at extremely low forces (<10pN) 

typical of what bone cells actually experience in vivo. Expansion of this technology to 

interrogate mechano-responsiveness in a broad range of cell types is a developmental goal of this 

grant. Significance: Understanding how osteocytes "perceive" and transduce mechanical signals 

may provide key new insights into bone physiology leading to the identification of novel 

therapeutic targets against bone loss due to aging and disease.
Page 70 of 103

1 R03 AR057518-01A1

Delayed pubertal development on the mechanism of bone loss at maturity

Yingling, Vanessa R

Temple University, Philadelphia, PA

$75,000

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. Osteoporosis is "a pediatric disease 

with geriatric consequences". Simply stated, suboptimal skeletal development in childhood and 

adolescence may result in decreased bone strength and an increase in lifetime fracture incidence. 

A delay in the onset of puberty (primary amenorrhea) correlates with both low bone mass; and an 

increased incidence of stress fracture. Suboptimal bone accrual may have long term 

consequences. Even with current treatment options as studies that treated amenorrheic dancers 

for 2 years with hormone replacement therapy found no difference in bone mineral density 

between treated and placebo groups. The most significant factors during development may be 

nutritional and lifestyle factors. Therefore, their overall goal is to ascertain the affect of delayed 

pubertal development on the mechanism of bone loss at maturity. Density measures alone, 

although widely used clinically, cannot identify osteoporotic subjects who will sustain fractures, 

due to the large overlap in bone mass measures in individuals with fractures and those without 

fractures. Other factors including bone size, architecture and material properties must be 

considered. They have recently developed a texture analysis approach using Gabor filters, which 

is capable of providing insight into bone structure from localized texture information on a pixel 

level. The texture approach is therefore a potentially powerful tool in analyzing trabecular bone 

texture where orientation, shape and architecture as well as density are the fundamental 

components. Their previous work was analyzing 2D images but they propose to transfers this 

approach to 3D images. This novel approach will indicate not only bone mass changes but 

changes in orientation which may be very significant later in life. In Aim #1, they will test the 

hypothesis that the mechanism and magnitude of bone loss in a mature animal is dependent on 

bone development. Specifically, delayed pubertal onset will alter the architecture of bone that 

will affect the mechanism of bone loss at maturity. Pubertal delay will be completed by 

gonadotropin releasing hormone antagonist (GnRH-antagonist) injections. At 50 days of age 

changes in bone morphology will be evaluated using a novel 3D texture analysis. The following 

biomarkers will be measured to assess the response of pubertal delay on systemic changes in 

bone metabolism osteocalcin (a marker of bone formation) and N-telopeptide of collagen type I 

(NTx) (a marker of bone resorption). Serum estradiol and IGF-1 will also be assayed to confirm 

the hormonal response to the protocol. Flourescent histomorphometry will assess bone formation 

rates on trabecular bone. At maturity (150 days of age) the experimental rats will undergo 

ovariectomy surgery to model post menopausal bone loss. Changes in bone morphology will be 

evaluated using static and dynamic histomorphometry, micro-CT and texture analysis. By using 

a systems approach relating environmentally induced delayed puberty to bone growth, they 

propose to gain a new understanding of the important relationship between growth and its 

variability and the bone structure they become heir to during the aging process. 
Page 71 of 103

NEUROLOGY/NEUROSCIENCES

5R21MH084041-02

Identification And Validation Of Human Hypothalamic Nuclei In-Vivo And Ex-Vivo Us

Makris, Nikolaos

Massachusetts General Hospital

$221,250

Hypothalamic nuclei will be identified in living humans using high field magnetic resonance 

imaging (MRI) (i.e., a 7 Tesla scanner) and in ex-vivo human hypothalamic tissue. The MRI 

results will be compared with postmortem human tissue to assure methodological validation. 

These hypothalamic nuclei are key regulators of autonomic and endocrine functions implicated 

in numerous psychiatric and medical disorders with known sex differences such as depression 

and schizophrenia. Understanding sex differences and the hypothalamic involvement in relation 

to neurological, psychiatric, cardiovascular, endocrine and sleep disorders is very relevant for 

public health in general and women's health in particular. There is increasing evidence 

regarding the importance of the hypothalamus for understanding women's health and sex 

differences in relation to neurological, psychiatric, endocrine and sleep disorders. In fact, 

hypothalamic nuclei, key regulators of autonomic and endocrine functions, are some of the most 

highly sexually dimorphic nuclei in the brain and implicated in psychiatric and medical disorders 

with known sex differences. They would argue that an understanding of hormonal effects on the 

brain and the regulation of other organs and/or systems, such as the cardiovascular and 

reproductive systems, are critical as downstream effects of hypothalamic activity. Thus an 

understanding of the neuroanatomy of hypothalamic nuclei and how they are differentially 

disrupted in men and women in specific disorders will contribute to elucidating sex differences 

in clinical medicine. However, the identification of hypothalamic nuclei in-vivo in humans has 

not been realized. This is important since studies have shown the association of the 

hypothalamus, endocrine dysfunction and sex differences in psychiatric disorders. In fact, the 

paraventricular hypothalamic nucleus (PVN) is enlarged in patients with major depressive 

disorder (MDD), in PVN neurons that are dense in corticotropin releasing hormone (CRH) and 

estrogen receptor (ER)1. In their recent work in schizophrenia (SCZ) they identified structural 

abnormalities using MRI in the hypothalamus particularly in the PVN in women. Furthermore, in 

healthy women they showed, using functional MRI, regulation of brain activity in hypothalamic 

nuclei such as the PVN, dependent on gonadal hormone changes over the menstrual cycle. The 

principal focus of this study is to use a new in-vivo methodology for the assessment of the 

hypothalamus comparing neuroimaging data using 7 Tesla magnetic resonance imaging (MRI) 

and human postmortem validation. The proposed study aims to identify the PVN in-vivo and exvivo in the human hypothalamus using high field MRI, to investigate the relationship of the MRI 

methodology and the histological technique, and to establish the correlates of the histological 

structures with the MRI representations. In addition to the PVN, which is critical for its role 

within the hypothalamic-pituitary-adrenal (HPA) axis and its dysfunction in MDD and SCZ, they 

will identify the supraoptic nucleus (SON), which will be used as a control region. Highresolution 7 Tesla MRI will be carried out in thirty healthy subjects, and four ex-vivo human 

hypothalamic samples. Their overarching goal is an innovative methodological one: to identify 

the PVN of the human hypothalamus in healthy adult women and men in-vivo. They expect this 

method, once defined, to be applied clinically in subjects with MDD and SCZ.
Page 72 of 103

5R21MH086731-02

Cellular And Molecular Basis Of Hippocampal Atrophy In Depressed Female Monkeys

Shively, Carol A.

Wake Forest University Health Sciences

$185,000

Depression is a significant health problem in the US, particularly in women, as 20% of 

reproductive-aged women experience clinically significant depression. Unfortunately very little 

research has been conducted in female animal models of depression. The use of the first primate 

model of adult depression in females proposed here, which has greater similarity to human 

neurobiology and depression than rodent models, will advance their understanding of the 

neurobiology of depression especially in women. Clinical and experimental studies suggest that 

hippocampal volumes may be smaller in individuals with depression, although the cellular 

mechanisms underlying this relationship are unclear. Stressful life events are associated with an 

increased risk of depression, and animal models, exposed to chronic stress have been used 

previously to investigate hippocampal shrinkage in depression. Although the data from 

preclinical stress models are compelling, the degree to which stress responses in animal models 

are relevant to human depression remains controversial, particularly since women are at two-fold 

greater risk of depression and the animal models are mostly male rodents. Evaluation of the 

causes of reduced hippocampal volume in an experimental model that more closely resembles 

human depression would be valuable. They have developed a primate model of depression in 

adult female cynomolgus monkeys which closely resembles human depression, and recently 

observed that depressed monkeys have relatively small anterior hippocampi. The overall goal of 

this proposal is to evaluate hippocampal morphologic, cellular, and molecular characteristics in 

depressed and nondepressed female monkeys to determine whether the smaller hippocampi of 

depressed female monkeys are accompanied by reductions in neutrophils and synaptic, spinous, 

and dendritic integrity. They have a unique and valuable collection of fixed, frozen hippocampi 

derived from the population of adult female monkeys in which the behavioral and physiological 

characteristics of depression were studied premortem for 4 years. Using the tissue from 8 

depressed and 8 nondepressed monkeys they will determine astrocyte, pyramidal, and granule 

neuron size and number, and protein and mRNA levels of markers of synaptic, spinous, and 

dendritic integrity in the cornu ammonis (CA) CA1, CA2, CA3, and DG of the anterior and 

posterior HC of behaviorally depressed and nondepressed monkeys. The results of this study will 

establish the use of the model in future investigations of the mechanisms of depression and the 

efficacy of interventions for depression. The research is particularly responsive to the FOA 

entitled 'Advancing Novel Science in Women's Health Research' (PAS-07-381). The results of 

the proposed study will be used in support of a competitive NIH application.

5R21NS066307-02

Sex-Specific Gene Regulation Of Neuronal Chloride Co-Transporter, Kcc2

Liedtke, Wolfgang B

Duke University

$195,000

Neuronal chloride dictates nerve cells' excitability, and is reduced in chronic pathological pain as 

well as in certain forms of epilepsy, diseases characterized by therapeutic refractoriness and 

strong female preponderance. Experiments are described that will elucidate the regulation of the 

dominant electroneutral chloride transporter of mature neurons, KCC2. Estrogen and xenobiotic 
Page 73 of 103

estrogen-mimetics will be used for stimulation of primary cortical neurons in culture, which will 

be maintained strictly separate for male vs. female, based on a novel methodology platform 

described here. Neurons derived from late-pregnancy embryos of rats and mice, the latter 

genetically encoded to lack functional estrogen-receptors, will be subjected to assays probing 

function and regulation of the kcc2 gene, namely reporter gene assays and measurement of 

neuronal chloride. Chronic pathological pain and certain epileptic syndromes are 

neuropsychiatric disorders that share an increased female prevalence and refractoriness to 

treatment. The latter feature is considered to be linked to pathologically increased neuronal 

excitability caused by increased neuronal chloride (Cl-), which in turn is rooted in downregulation of the dominant neuronal Cl--transporter, KCC2, which extrudes Cl-. Here they 

propose experiments to elucidate sex-specific regulation of the kcc2 gene by estrogens, based on 

a hypothesis that neuronal Cl- is dysregulated in response to neuronal injury in a sexually 

dimorphic manner, with the consequence of rendering women more susceptible to the above 

diseases. They have obtained exciting preliminary results (1) showing that kcc2 transcription is 

regulated by the repressor REST/NRSF which binds to a novel RE1/NRSE DNA binding site in 

kcc2 regulatory regions, (2) demonstrating this regulation to underlie the early developmental 

transformation of GABAergic transmission from excitatory to inhibitory, (3) developing a novel 

method to culture cortical primary neurons from individual rat E17 embryos which are being 

sex-typed by X-and Y-chromosome specific DNA markers. The latter method, straightforward 

yet possibly a groundbreaking novelty, permits strictly separate female vs. male primary cortical 

neuronal culture. They intend to elaborate molecular mechanisms how neuronal Cl- and KCC2 

are regulated sex-specifically by exposing male vs. female neurons to 17--estradiol and 

xenobiotic estrogen-mimetics. For this, they will electroporate kcc2 reporter gene constructs, 

wildtype and mutated for binding sites, driving a secreted luciferase reporter, which will 

facilitate establishment of a time-course of kcc2 transcription. For direct determination of Cl-, 

the fluorescent Cl--indicator clomeleon will be co-transfected. Cultures will be exposed to 

physiologically relevant concentrations of estradiol and practically relevant concentrations of 

xeno-estrogens (coumestrol, bisphenol-A, dieldrin). Use of the latter compounds will allow us to 

address modulation of estrogen responses by these ubiquitous compounds. Any sex-specific 

regulation will be confirmed in primary cultures derived from gene-targeted mice (estrogenreceptor (ER)-a, - and non-classical-ER-knockin). These experiments will be conducted in a 

highly collaborative environment at Duke University, involving molecular and physiology 

neuroscience labs, in addition molecular endocrinology and environmental toxicology input. 

Results can be expected to shed new light on a fundamental matter, neuronal Cl--regulation, 

which very likely has sex-specific regulation as a basis for increased female prevalence in 

therapy-refractory neuropsychiatric diseases.

1 R21 NS071210-01

Sex differences in the CNS during disease

Voskuhl, Rhonda R

University of California Los Angeles, Los Angeles, CA

$231,000

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 
Page 74 of 103

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. 

NUTRITION

Y1-CN-501054

National Food and Nutrient Analysis Program (NFNAP)

NCI-USDA

NCI/USDA, Bethesda, MD

$50,000

The NFNAP is a research program that seeks to achieve sound estimates of dietary components 

and thus, improvements in nutrient values with particular focus on components with possible 

roles in human health. The project, directed by the Nutrient Data Laboratory (NDL), 

Agricultural Research Service, USDA, was initiated in 1997 and recently renewed in 

collaboration with the NIH National Cancer Institute and the Office of Dietary Supplements, 

ORWH, and other supporting NIH Offices, Institutes, and the FDA. The primary outcome of the 

program will be a body of nutrient data representative of the U.S. population intake and 

consumption patterns with unprecedented analytical quality. This is a collaborative, 

interdisciplinary project with the NFNAP. Specifically, the two leading causes of death in 

women in the U.S. are: (1) cardiovascular disease; and, (2) cancer. The NFNAP may prove 

particularly relevant to these women’s health issues because the food consumption and 

composition databases target those foods that are major contributors of public health significance 

in the U.S. Specifically, the five objectives of the NFNAP are to: (1) Sample and analyze 

selected Key Foods; (2) Institute a monitoring program for Key Foods; (3) Develop databases 

for foods consumed by U.S. ethnic subpopulations; (4) Develop and update databases for 

bioactive food components; and (5) Develop and validate databases for dietary supplement 

composition. Moreover, the NFNAP may be significant to research on women’s health on 

several different levels. Better estimates of the mean nutrient content of foods and variance 
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indicators will permit more accurate assessment of nutrient intakes by individuals. This will 

improve the ability to detect etiologic relationships, delineate biologic mechanisms, assess time 

trends in nutrient intake, and define populations at nutritional risk. Further, the NFNAP may 

provide background data supporting nutritional guidance and communications focused 

specifically on women.

OBESITY/OVERWEIGHT

5R21HL097252-02

Intervening On Spontaneous Physical Activity To Prevent Weight Regain In Women

Nicklas, Barbara J

Wake Forest University Health Sciences

$156,894

Weight loss programs using caloric restriction and regular, structured exercise can lead to a 

reduction in physical activity performed outside of the planned exercise sessions. This study will 

test whether or not women reduce their spontaneous daily physical activity more than men with 

weight loss, and whether this reduction can be prevented by using self-monitoring, thereby 

slowing or preventing weight regain. Since reductions in spontaneous physical activity could 

potentially negate the intent of a structured exercise program for weight loss therapy, it would be 

important to know whether recommendations for weight loss maintenance in women should 

include promotion of spontaneous physical activity, rather than structured exercise, during and 

following a period of intensive weight loss. Recommendations for more effective long-term 

weight loss strategies may need to consider the role of gender differences. If, as shown in female 

vs. male animal models, negative energy balance resulting in weight loss results in greater 

compensatory reductions in energy expenditure in women compared to men, obesity treatments 

may need to be tailored in women to override these reductions in total energy expenditure. Their 

approach focuses on a behavioral strategy (self-monitoring) to eliminate the compensatory 

reduction in non-exercise 'spontaneous' physical activity (SPA) seen in women who lose weight 

by means of a hypocaloric diet and structured exercise training. Their long-term research goal is 

to establish empirical evidence for innovative treatment options that are more effective in 

producing weight loss and preventing weight regain in women. The main goal of this pilot is to 

provide preliminary data and effect estimates to begin to test their overall hypothesis that 

prevention of weight loss-induced reductions in SPA will be more beneficial for long-term 

maintenance of weight loss in women than in men. They propose to conduct a pilot study using a 

2-arm, 10-month design in 72 obese, older (55-70 yrs) men and women (n=36 per group). 

Participants will be randomized to a 5-month standardized weight loss intervention involving a 

hypocaloric diet and aerobic exercise (DIET+EX) or to the same weight loss intervention with 

addition of a behavioral component that targets self-monitoring (SM) of SPA (SM+DIET+EX), 

and then followed for another 5 months after weight loss. The specific aims of this R21 

exploratory/developmental application are: Primary-To examine whether SPA self- monitoring 

results in less body weight regain in the follow-up phase in both men and women; Secondary-To 

examine whether: 1) women regain more weight than men in the follow-up phase; 2) SPA selfmonitoring and gender have an effect on change in weight in the intensive weight loss phase; 3) 

SPA self-monitoring and gender have an effect on change in SPA in the intensive weight loss 

phase; 4) there is an association between SPA changes in the weight loss phase and weight 
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regain in the follow-up phase. They anticipate that the results will lead to a larger and longer trial 

to definitively test their hypothesis, which could potentially provide evidence against the current 

standard of care (i.e., exclusive prescription of structured moderate-intensity exercise) for obesity 

therapy in women and may lead to sex-specific treatment guidelines.

PAIN

5R21DE019267-02

Sex Differences In Acute Pain And Analgesic Responses: Psychosocial And Genetic I

Hastie, Barbara A

University Of Florida

$181,294

Pain is one of the most costly and pervasive public health problems in the United States, and 

women are at increased risk for under-treatment of pain. This study will use a common acute 

clinical pain model to identify and characterize psychosocial, physiological and genetic factors 

that contribute to sex differences in pain perception, analgesia and side effects. The ultimate goal 

is to develop translational research that will reduce the increased burden of clinical pain in 

women through the development of tailored interventions designed to enhance the quality of life 

for women, consistent with priorities of the NIH Office of Research on Women's Health. Pain is 

one of the most costly and pervasive public health problems, with women and minorities facing 

increased risk for under-treated and mismanaged pain. Women, compared to men, report more 

frequent and intense pain and have increased prevalence of debilitating pain across a multitude of 

conditions. Women also represent the majority of the 40 million outpatient and ambulatory 

surgeries conducted each year. Acute post- operative pain and under-treatment of pain are welldocumented and lead to prolonged recovery and potentially to development of chronic long-term 

pain conditions. Despite incongruent findings of sex differences in analgesic efficacy, consistent 

reports show that women experience between 30%-75% more adverse drug reactions (ADRs) 

compared to men. ADRs can lead to life-threatening complications, discontinuation of pain 

treatment, prolonged recovery and non-compliance. Recent pharmacogenomic studies have 

demonstrated that genotype may contribute to sex differences in pharmacokinetic (PK) and 

pharmacodynamic (PD) responses to certain drugs. Genetic and nongenetic contributions to sex 

differences in opioid analgesia, related side effects and treatment outcome have received limited 

attention in the field of pain research. This study will use a common acute clinical pain model to 

identify and characterize psychosocial, physiological and genetic factors that contribute to sex 

differences in pain perception, analgesia and side effects. Aim 1 will determine sex differences in 

perceptual and physiological responses to acute post-operative pain and will examine how those 

are related to genetic, pre-operative psychophysical and psychosocial factors. Aim 2 will 

determine sex differences in opioid analgesia and side effects and will examine genetic, PK, PD, 

and psychosocial factors that explain group differences in analgesic responses. 140 male and 

female patients (age range 16-45) who undergo third molar extraction will be included in this 

study. Preoperatively, they will assess experimental pain responses and psychosocial measures. 

They will monitor post-operative pain levels along with PK/PD responses to the opioid fentanyl. 

They will examine sex differences in post-operative pain, analgesic responses and side effects 

immediately and for several hours post-surgery and for 3 days post-procedure. The study is 

designed to build a foundation for a R01 grant proposal supporting an independent line of 
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clinically-relevant experimental pain research. This project will enhance understanding of 

translational research in pain as well as biopsychosocial factors that contribute to health 

disparities in pain and its treatment, particularly for women. Additionally, this study will provide 

insight into the complex genetic, PK/PD processes involved in post- operative pain and analgesic 

responses and will elucidate biopsychosocial contributions to sex differences in pain and side 

effects. The ultimate goal is to develop translational research that will reduce the increased 

burden of clinical pain in women through the development of tailored interventions designed to 

enhance the quality of life for women, consistent with priorities of the NIH Office of Research 

on Women's Health.

1 R03 AR057489-01A1

Epidemiology of Patellofemoral Pain Syndrome: Identifying Gender Specific Risk Factors

Boling, Michelle Clara

University of North Florida, Jacksonville, FL

$72,866

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 

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 
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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. 

5 R21 HD053510-03

Pain and Endometriosis: Effects on Ectopic Cyst Innervation and Axons

Bove, Geoffrey M.

University of New England, Biddeford, ME

$171,069

In these studies they plan to develop their recently developed model of sciatic endometriosis to 

make novel inquiries regarding the etiology of endometriosis-related pain. The information that 

this study will yield stands to improve diagnostic awareness and mechanistic understanding, and 

thus therapeutic approaches, of the treatment of the symptoms of endometriosis. As a result of 

this research, consideration and specific examination of nerves within the pelvis during ablative 

laparoscopic techniques may become an important additional diagnostic procedure for women 

with endometriosis. Women with endometriosis often have significant pain. Modern studies 

have implicated the neo-innervation of endometrial cysts as a primary source of this pain. 

However, the presence of nerve fibers does not necessarily specify their function and cannot 

determine whether, or in which situations, they are active. There has been no investigation to 

functionally characterize the effect of endometrial lesions on nerves or on axons. Their 

laboratory has focused on the effects of inflammation on axons. They have shown that nerve 

inflammation induces ectopic mechanical sensitivity of nociceptor axons, which are not normally 

sensitive. Their data also indicate that nerve inflammation induces ongoing activity that arises 

from both the inflamed site and / or the cell body, and that sympathetic neuronal activity is 

decreased during nerve inflammation. Recently they adapted the model of rat endometriosis to 

involve the sciatic nerve. This model is very similar to the rat endometriosis model where a 

section of uterus is transplanted to a intraperitoneal site. In preliminary data, a uterine section 

was transplanted to the sciatic nerve. Three complimentary electrophysiological methods are 

proposed to determine the characteristics of the effect of uterus, endometrium, and myometrium 

on the sciatic nerve. First, the proportion of through-conducting axons will be determined. Then, 

teased fiber recordings will be made from the dorsal roots in some experiments and from the 

distal end of peripheral nerves in other experiments. This combination of methods offers the 

advantage that sensory and sympathetic axons that pass through the cyst, as well as those 

innervating the cyst, can be studied. They will determine if the axons passing in close proximity 

to the cyst or directly innervating the cyst develop ongoing activity and / or mechanical 

sensitivity. Recordings will be made 3 months post surgically, after the cysts become stable, and 

the results compared to myometrium or fat transplant, and unoperated nerves. Because 

preliminary results revealed the presence of intraneural immune cells, they will determine 

whether the lesions of endometriosis damage axons. Importantly, they will use not only full 

thickness uterus, but also isolated endometrium and myometrium, and evaluate the viability of 

these specific tissues to form cysts. Using immunohistological methods, they will determine the 

extent of neutrophil and macrophage invasion of the nerve-uterus complex. They will also 

determine if axons are damaged using ninjurin and fluoro-jade, assessing the presence in both 

axons and dorsal root ganglion cells. These studies will determine the function and thus the 

importance of the ectopic innervation of endometrial cysts, as well as the effects of the lesions on 
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through-conducting axons. The results of this study will impacts the understanding of 

endometriosis pain and seed further research into the pain mechanisms of endometriosis. 

1 K23 NS070891-01

Functional Networks in Migraine

Schwedt, Todd

Washington University, Saint Louis, MO

$163,523

Migraine is an exceedingly common disease, affecting 12% of the population. Migraine results 

in substantial disability due to headache pain, hypersensitivities to environmental stimuli, and 

skin sensitization. Unfortunately, migraine is poorly understood and can be difficult to treat. This 

study will employ advanced neuroimaging techniques to investigate functional networks in the 

brain that may explain the relationship between migraine headache and hypersensitivities, as 

well as how environmental stimuli trigger a migraine attack. Description of these functional 

networks will allow for future investigations into methods to normalize or block activation of 

these networks, methods that may reduce migraine symptoms and improve the lives of millions 

of migraine sufferers. Migraine attacks are characterized by moderate to severe ain, nausea, 

vomiting, increased sensitivity to lights, sounds and odors, and cutaneous allodynia. Migraine, 

which afflicts 36 million Americans, causes substantial individual and societal burden. Although 

individual migraine attacks last for several hours to a few days, there is often persistence of 

hypersensitivities such as photophobia, phonophobia and osmophobia and cutaneous 

sensitization between migraine attacks. Furthermore, migraine attacks can be triggered by light, 

noise and odors. The mechanisms for interictal persistence of these symptoms and the 

mechanisms by which environmental stimuli trigger migraine attacks are unknown. In this set of 

experiments they address these associations by using functional magnetic resonance imaging to 

investigate functional networks in episodic and chronic migraine subjects. The specific aims will 

test the following hypotheses: 1) stimulus-induced deactivation of the default mode network is 

less in migraine subjects compared to non-migraine controls; 2) migraineurs have stronger 

functional connectivity among regions of the brain responsible for pain processing and between 

these pain processing regions and those responsible for processing of auditory, visual and 

olfactory stimuli; 3) abnormal default mode network deactivation and stronger functional 

connectivity among pain regions and between pain regions and regions of the auditory, visual 

and olfactory networks are positively associated with greater migraine burden. It is necessary to 

establish and assess functional networks in migraine so that future studies can investigate 

methods to normalize potentially aberrant networks and block activation of these networks, 

actions that may prevent and alleviate migraine symptoms. The candidate is an Assistant 

Professor of Neurology and Anesthesiology and Director of the Washington University 

Headache Center in St. Louis, Missouri. The candidate's short-term goal is to enhance his 

functional neuroimaging skills so that he can transition from mentored to independent patientoriented research employing functional imaging to investigate the pain and associated symptoms 

(hypersensitivities to and triggering of migraine by sound, light and odors and cutaneous 

sensitization) of migraine. Once the relationships between migraine headache and these 

associated symptoms are described, the longer-term goal is to explore mechanisms by which to 

normalize these relationships or block activation of functional networks that lead to migraine 

symptoms. The multidisciplinary team of world-class mentors and the extensive intellectual and 
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physical resources available at Washington University will optimize the candidate's training 

experience and likelihood for successful transition to independent research. 

REPRODUCTIVE HEALTH/DEVELOPMENTAL BIOLOGY

5R21AI083954-02

Advancing Research On The Sexually Transmitted Female 'Nuisance' Pathogen Trichom

Carlton, Jane

New York University School Of Medicine

$211,250

Trichomoniasis, caused by the eukaryotic parasite Trichomonas vaginalis, is the most common, 

non-viral, sexually transmitted infection worldwide, but long considered a female 'nuisance' 

disease. The goal of this project is to determine the genetic diversity of the parasite in women 

attending STD clinics in New York City, and to use these extant isolates in the development of a 

model system for the study of colonization of the vagina. Trichomoniasis is the most common 

non-viral STD, estimated to cause ~174 million infections world-wide each year. The 

Trichomonas vaginalis parasite resides in the urogenital tract of both sexes and can cause 

vaginitis in women and urethritis and prostatitis in men. However, the disease is known more as 

a female 'nuisance' condition, which has resulted in a lack of scientific and medical attention and 

scant interest by public health officials in developing trichomoniasis control programs. Acute 

infections among women are associated with pelvic inflammatory disease and adverse pregnancy 

outcomes. Most alarming is the recognition that T. vaginalis infection appears to increase 

women's susceptibility to HIV-1 infection. Because of the association between T. vaginalis and 

risk for HIV-1 acquisition, interventions to reduce T. vaginalis infection and transmission would 

likely result in fewer HIV-1 infections. Completion of the T. vaginalis genome sequence in 2007 

has significantly increased their knowledge concerning the biology and mechanisms of 

pathogenesis of the parasite, but significant gaps remain. In particular, the genetic diversity of 

the parasite is not known, i.e. whether the parasite is maintained as a clonal population, or 

whether genetic exchange occurs between parasites in the urogenital tract. The extent of genetic 

diversity has implications for the control of the disease, for example it determines how virulent 

parasites spread or how they may evade a vaccine. The focus of this R21 proposal is to examine 

the genetic diversity of T. vaginalis infecting women attending eight New York City Bureau of 

STD clinics in inner city areas, and to use some of these isolates to develop a standardized and 

accessible in vitro model system for the study of colonization of the vagina by the parasite. A 

panel of polymorphic genetic markers - microsatellites and single copy genes - will be developed 

using the T. vaginalis genome sequence, and used to genotype T. vaginalis isolates identified in 

vaginal swabs taken from women attending the clinics. Knowledge of the genetic diversity and 

colonization characteristics of the parasite will provide important data points for subsequent 

studies, for example determining associations between T. vaginalis genotypes and the 

commensal microbes that make up the vaginal 'microbiome'.
Page 81 of 103

3R21HD059015-02S1

The Role Of Gpr54 Signaling In Pubertal Disorders

Bianco, Suzy Drumond Carvalho

University Of Miami School Of Medicine

$65,912

The long term goal of this project is to identify factors that regulate the timing of pubertal onset 

and reproductive maturation. The identification of GPR54, a G-protein coupled receptor, and its 

ligand, kisspeptin, as upstream regulators of GnRH secretion has led to intense research to 

elucidate their roles in the regulation of the reproductive axis. Inactivating mutations in GPR54 

cause failure to undergo puberty and infertility. In contrast, early stimulation of this receptor 

triggers precocious puberty in mice. Their preliminary results indicate that GPR54 is 

desensitized and internalized in response to continuous kisspeptin stimulation, and that a GPR54 

amino acid substitution identified in a female patient with central precocious puberty (a disorder 

with disproportionately high female incidence) increases GPR54 responsiveness by delaying the 

desensitization of the receptor. Thus, they hypothesize that the timing of signaling and 

desensitization of GPR54 is critical for its role in controlling puberty and reproduction, and that 

amino acid substitutions in GPR54 may affect its responsiveness by interfering with signaling or 

desensitization, thereby contributing to the clinical presentation. Although G-protein coupled 

receptor desensitization is generally strongly regulated, no data have been published on GPR54 

desensitization. The short term goal of this project is to define the mechanisms underlying 

GPR54 desensitization, in order to understand how genetic mutations of this receptor affect these 

mechanisms and hence the timing of pubertal onset and sexual maturation. Specifically, the aims 

of this proposal are to: (1) Define the mechanisms of GPR54 desensitization, focusing on the 

roles of phosphorylation and arrestin recruitment; (2) Define the mechanisms of GPR54 

internalization, focusing on the roles of arrestin, dynamin, and clathrin; and (3) Define the fate of 

the internalized GPR54, to determine whether the receptor is directed to lysosomal degradation 

or recycled back to the plasma membrane. In each case, the effects of two mutations in GPR54, 

one identified in a patient with precocious puberty, and the other in a patient with 

hypogonadotropic hypogonadism, on these pathways will be determined. A thorough 

understanding of the mechanisms underlying GPR54 signaling may uncover the basis of gender 

differences in normal and abnormal pubertal development, as well as reveal a new array of 

potential targets of pharmacological manipulation for the treatment and prevention of abnormal 

pubertal development and possibly other reproductive disorders. Role of GPR54 Signaling in 

Pubertal Disorders Narrative The goal of this project is to define the mechanisms underlying the 

regulation of GPR54 receptor signaling and desensitization, in order to understand how genetic 

mutations of this receptor affect these mechanisms and hence the timing of pubertal onset and 

sexual maturation. These studies are expected to offer important contributions to their 

understanding of the mechanisms underlying the reproductive disorders in the patients carrying 

the mutations. These insights, in turn, may contribute to future development of therapies 

designed to modulate the timing of puberty by manipulating the kisspeptin-GPR54 signaling 

system.
Page 82 of 103

5R21HD061644-02

Physiological Reactivity To Acute Stress During Pregnancy

Christian, Lisa Michelle

Ohio State University

$221,012

This study will fill important gaps in their knowledge regarding physiological adaption during 

pregnancy and effects of race on such adaptation. Information gained from this study will 

provide the groundwork for the following: 1) identification of women at greater risk of negative 

perinatal outcomes; 2) describing physiological mechanisms underlying the link between stress 

and risk of preterm delivery; and 3) providing interventions designed to reduce the effects of 

stress and promote healthy pregnancy and fetal development. Preterm delivery, an increasingly 

frequent occurrence in the United States, is associated with significant family burden and an 

estimated societal cost of at least $26 billion per year. In the U.S., the preterm birth rate is 12-

13% as compared to 5-9% in other developed countries. Persistent racial disparities contribute to 

this discrepancy. Psychosocial stress and related physiological sequelae may contribute to 

preterm birth overall, as well as to racial disparities in preterm birth. The experience of chronic 

stress, such as that conferred by racial minority status, may sensitize physiological stress 

responses. Indeed, as compared to Caucasians, African-Americans exhibit greater cardiovascular 

reactivity to a variety of acute stressors. Importantly, blood pressure, glucocorticoid, and 

catecholamine responses to acute stress are attenuated during healthy pregnancy as compared to 

nonpregnancy. This adaptation may protect the mother and fetus from potentially detrimental 

effects of maternal physiological activation. Thus, women who exhibit greater and more 

extended physiological reactions to everyday stressors may be at increased risk for negative 

perinatal outcomes. Notably, no studies of acute stress during pregnancy have examined 

inflammatory immune responses or mechanisms underlying blood pressure change (i.e., cardiac 

output, total peripheral resistance). Moreover, limited information is available regarding effects 

of race on physiological adaptation to pregnancy. The current study will address important gaps 

in the literature by examining cardiovascular, endocrine, and immune reactivity to acute stress 

among 40 healthy pregnant women (20 Caucasian, 20 African-American) and 40 

demographically matched nonpregnant control women. This research is designed to ultimately 

lead to the identification of women at greater risk for negative perinatal outcomes and 

elucidation of mechanisms underlying increased risk, providing a basis for individualized health 

care services. Specific Aim #1: To utilize more comprehensive and advanced methodology to 

assess physiological reactivity during pregnancy versus nonpregnancy, including measures of 

inflammation, impedance cardiography, and glucocorticoid receptor function. Hypothesis #1: 

Pregnant women will show attenuated physiological responses to acute stress as compared to 

nonpregnant women. Specific Aim #2: To examine racial differences in physiological reactivity 

during pregnancy versus nonpregnancy. Hypothesis #2: As compared to Caucasian women, 

African-American women will exhibit greater physiological reactivity to stress during pregnancy 

and nonpregnancy. Specific Aim #3: To examine psychosocial correlates of physiological 

reactivity during pregnancy and nonpregnancy. Hypothesis #3: Women reporting greater distress 

will exhibit greater physiological reactivity during pregnancy and nonpregnancy. Specific Aim 

#4: To examine associations between physiological reactivity and length of gestation. Hypothesis 

#4: Greater physiological reactivity to acute stress will predict shorter gestational length.
Page 83 of 103

1R03HD061853-01A1

Upstream Regulation Of Kiss1 Cells

De La Iglesia, Horacio O

University Of Washington

$78,000

Ovulation depends on a surge in the release of luteinizing hormone (LH), which in turn depends 

on a surge of gonadotropin-releasing hormone (GnRH). In recent years, kisspeptin (KISS) has 

emerged as the most potent stimulator of GnRH and a key regulator of reproductive development 

and health in vertebrates, including humans. In females, KISS signaling to GnRH cells is critical 

for the induction of the LH surge. Despite the central role of KISS in reproduction and 

specifically in female reproductive development and fertility, little is known about the upstream 

regulators of neurons expressing Kiss1, the gene coding for KISS. Here they present preliminary 

results that indicate that Kiss1 expression and the expression of c-fos within Kiss1 neurons in 

female mice is under circadian regulation, and this regulation is dependent on the presence of 

high ovarian estrogen levels. The overall goal of this proposal is to determine the pathways by 

which the circadian system may regulate the activity of Kiss1 neurons. Their laboratory has 

developed a rat model of circadian desynchronization in which independent circadian outputs are 

associated with the desynchronized activity of anatomically identifiable subregions of the 

hypothalamic suprachiasmatic nucleus(SCN), the site of the mammalian master circadian 

pacemaker. Their preliminary data on this forced desynchronized rat model indicates that the 

gating of the luteinizing hormone (LH) surge is associated withthe activity of the dorsomedial 

(dm) SCN irrespective of the activity of the ventrolateral (vl) SCN. Because the dmSCN is the 

main source of vasopressinergic efferent fibers, their hypothesis is that vasopressin (VP)release 

is a critical SCN signal to induce the LH surge and therefore to activate Kiss1 neurons in a 

circadianpattern. They propose experiments that test specific predictions of this hypothesis. They 

will test the prediction that SCN vasopressinergic fibers innervate Kiss1-expressing cells and that 

innervation of the Kiss1 neuronal network by SCN efferent fibers is critical to sustain the 

circadian regulation of Kiss1 and of c-fos expression within Kiss1 neurons, which are 

concomitant with the LH surge. They will use unilateral lesions of the SCN to ipsilaterally 

deplete the anteroventral periventricular nucleus of SCN efferent fibers. In these animals they 

will assess the level of asymmetric VP innervation of Kiss1neurons as well as the asymmetry in 

the circadian regulation of Kiss1 expression and c-fos expression within Kiss1 cells. Their 

proposed studies will characterize the pathways and mechanisms by which the activity of 

theKiss1 neuronal network is regulated. Specifically, they will determine how a critical 

component of the mechanisms leading to ovulation such as the circadian system regulates gene 

expression within Kiss1 cells. Because the activity of these neurons and the release of KISS are 

essential for normal ovulation, understanding the upstream regulators of Kiss1 neurons will be 

key to developing therapies to treat disorders of the hypothalamo-pituitary-ovarian axis.

5R21HD059074-02

A Study Of The Factors Influencing Women's Decision About Childbirth

Regan, Mary J

University Of Maryland Baltimore

$187,063

This project in focused on building knowledge about what women want from their birthing 

experience and what informs their choices about mode of birth. This knowledge is essential if 
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they are to understand the role of maternal demand in use of CS. Their data will inform public 

health policy concerned with both supporting maternal choice and ensuring long term maternalchild health by reducing the risks associated with childbirth. This study is part of a systematic 

program of research dedicated to improving women's health and satisfaction with their birthing 

experience. Cesarean section (CS) is currently used at over twice the rate recommended by the 

World Health Organization (CDC, 2006); use of the procedure has almost doubled in the last two 

decades for reasons that are as yet poorly understood. Overutilization results in avoidable 

morbidity and mortality and higher health costs related to childbirth. Many causes for the 

increased use of CS have been suggested, including growth in the number of 'maternal requests' -

- healthy women asking for CS in the absence of medical indications. An NIH expert panel 

explored maternal request CS and concluded that at this time there is insufficient evidence to 

warrant CS on maternal demand without medical indications and recommended 'increased 

research devoted to strategies to predict and influence the likelihood of successful vaginal birth' 

(NIH, 2006, p. 20). Using the same data, the American College of Obstetrics and Gynecologists 

(ACOG) concluded that there is no reason to deny a surgical birth to a healthy mother as long as 

she is well-informed (ACOG, 2003). The divergence between these positions points to a critical 

gap in knowledge about the factors that drive CS rates, including the influence of maternal 

demand on the use of CS. Despite this recent focus on maternal demand, there is scant research 

on what women want from their birthing experience, including their reasons for choosing one 

mode of childbirth over another. The purpose of their proposed research is to answer the 

question: what factors influence women's decisions about how their babies will be born? 

Women's hopes and desires for their first birth experience are influenced by what they know -

both consciously and unconsciously. Because people are only partly aware of the attitudes and 

beliefs that inform their hopes and desires, this proposal will use three methods of data 

collection. The first is a projective method commonly used in the social sciences to access 

knowledge that exists outside of consciousness. The second is a focus group method that 

provides a venue for birthing women to articulate the conscious basis for their ideas about 

childbirth and allow participants to compare their ideas with others. Third, all women will be 

interviewed after the baby is born to build understanding about how their experiences influence 

future birthing choices the women make. Participants will be 50 primigravid women with 

uncomplicated pregnancies aged 21 or older. This proposal builds on the researchers' previous 

work related to the use of CS. It is one step in a defined program of research directed towards 

improving the health of mothers and their children by optimizing care during pregnancy, labor 

and birth.

5R21ES016846-02

Modulation Of Pah Ovarian Toxicity By Biotransformation Enzyme Polymorphisms

Luderer, Ulrike

University Of California Irvine

$189,823

The primary and long-term goal of this research is to understand how toxicants cause ovarian 

dysfunction so that they can prevent it. These studies will provide insights that will help us to 

understand why some women are more sensitive to ovarian toxicants than other women. In so 

doing, they will also lay the groundwork for possible interventions to protect against ovarian 

dysfunction. Infertility or impaired fecundity affects 12% of American women. Ovarian 

dysfunction, including premature ovarian failure is a major cause of infertility. It is likely that 
Page 85 of 103

exposure to environmental toxicants is responsible for many more cases of impaired ovarian 

function than is currently appreciated. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous 

environmental contaminants, which are known to impair ovarian function and cause ovarian 

failure in rodents and are probable ovarian toxicants in women. Tobacco smoke, foods, and air 

pollution are among the sources of exposure to PAHs. The mechanistic basis for interindividual 

variation in susceptibility to PAH ovarian toxicity is not understood, but polymorphisms in 

enzymes that metabolize PAHs likely play an important role. The work outlined in this proposal 

will demonstrate the feasibility of a larger study to test the hypothesis that genetic variations in 

Phase 1 and Phase 2 biotransformation enzymes involved in metabolizing PAHs modulate the 

ovarian toxicity of PAHs in women. Specific Aim 1: To test the feasibility of prospectively 

measuring time to pregnancy and PAH exposure and of using genomewide genotyping methods 

to determine PAH biotransformation enzyme polymorphisms for a study analyzing the 

associations between PAH exposure and biotransformation enzyme polymorphisms and 

fecundability (time to pregnancy). Specific Aim 2: To test the feasibility of using microelectronic 

dipstick monitors to measure daily urinary reproductive hormone concentrations over multiple 

menstrual cycles for study of the associations between PAH metabolizing enzyme 

polymorphisms and PAH exposure and menstrual cycle abnormalities. Specific Aim 3: To pilot 

test serum anti-M|llerian hormone, follicle stimulating hormone, and inhibin B concentrations as 

markers of ovarian reserve for study of the associations between PAH exposure and diminished 

ovarian reserve.

5R03NS063233-02

Neuroactive Steroids And Seizure Control During Pregnancy In Women With Epilepsy

Pennell, Page Buckhannan

Brigham And Women's Hospital

$101,800

Treating women with epilepsy during pregnancy requires a precarious balance of controlling the 

mother's seizures without exposing the developing fetus to more anticonvulsant medication than 

necessary. During pregnancy, the rising sex steroid hormones and their metabolic byproducts 

may directly influence seizure control; this study will analyze blood samples already obtained in 

women with epilepsy during pregnancy to examine whether women with increased seizures have 

alterations in neuroactive steroid levels. These findings could lead to the development of novel 

treatment strategies for women with epilepsy during pregnancy, such as use of supplemental 

progesterone, to improve mother and child health outcomes. Epilepsy is a common disorder, 

affecting approximately 1.3 million women of child-bearing age in the United States. Seizures 

during pregnancy can cause increased risks to both the mother and fetus. These risks have to be 

balanced against the known teratogenic effects of antiepileptic drugs (AEDs). During pregnancy, 

the sex steroid hormones estradiol and progesterone increase dramatically. Sex steroid hormones 

and the metabolic byproducts that are capable of modifying neural activity are classified as 

neuroactive steroids (NAS). Animal models demonstrate modulation of seizure activity by the 

NAS 17¿-estradiol (EST), progesterone (PROG), and allopregnanolone (ALLO). In women, 

fluctuations in these NAS have been implicated in seizure control in the non-pregnant state, with 

worsening seizures at certain times of the menstrual cycle (catamenial epilepsy). Human studies 

have demonstrated an increase in seizure frequency with elevated EST/PROG ratios and with 

declining or low PROG levels. This has not been studied during pregnancy in women with 

epilepsy. This proposed study will utilize serum samples (n=810 samples) already collected from 
Page 86 of 103

135 women with epilepsy during different stages of pregnancy during a Specialized Center of 

Research in Women and Gender Issues program project grant. These women were enrolled 

prospectively with tracking of seizures and medications. Collection of plasma samples occurred 

at multiple points in each trimester. Based on variable points of enrollment (< 20 weeks 

gestation), they have increased observations/samples in the later trimesters of pregnancy. Seizure 

frequency will be analyzed during the second and third trimesters of pregnancy and compared to 

the nonpregnant baseline for each subject. Consistent with the R03 mechanism, the current 

application will extend the analysis of these existing data/samples via measurement of the 

neuroactive steroids EST, PROG, and ALLO. The working hypotheses are 1) during pregnancy, 

changing concentrations of EST and PROG influence seizure control; 2) the progesterone 

metabolite, ALLO, mediates the seizure-reducing effect of PROG. The following will be 

analyzed in relationship to change in seizure frequency during pregnancy: EST/PROG ratio, the

rate of rise of PROG, and the rate of rise of ALLO. Additionally, given that labor and delivery is 

a particularly vulnerable time for increased seizures; ALLO and PROG levels will be compared 

between women who had peripartum seizures and those who did not. This study can ultimately 

lead to a better understanding of the NAS regulation of seizure control during pregnancy. 

Insights gained from this study could provide the impetus for further development of NAS 

analogs, with treatment benefits extending to both genders and across all ages. During 

pregnancy, treatment with supplemental progesterone could allow for decreased levels of fetal 

exposure to AEDs in utero, with improved seizure control and reduced anatomical and 

neurodevelopmental teratogenicity.

1 R01 HD064398-01

Genetic Determinants of Uterine Fibroids in African-American and Caucasian Women

Aissani, Brahim

University of Alabama, Birmingham, AL

$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 
Page 87 of 103

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 

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 U10 HD054215-05

The Cleveland Clinic Clinical Site

Barber, Matthew

Cleveland Clinic, Cleveland, OH

$25,000

Pelvic floor disorders (PFD) including urinary incontinence, pelvic organ prolapse (POP), and 

fecal incontinence affect a substantial proportion of women in the U.S. PFD result in significant 

psychosocial costs to an individual and their aggregate social and economic costs to society are 

enormous. Despite their substantial health impact, the quality of the evidence supporting most of 

the commonly used treatments, especially surgical interventions, is limited by the lack of 

standardization of diagnostic and therapeutic interventions, use of non-standardized and nonvalidated outcome measures, poor quality research designs, and inadequate power to detect 

clinically meaningful differences. The long-term objective of the Pelvic Floor Disorders Network 

(PFDN) is to identify optimum diagnosis and management strategies for women with PFD using 

the highest quality research methods available. The specific aims of this application are: 1) to 

demonstrate that the Cleveland Clinic Foundation (CCF) possesses the personnel, patient, 

clinical, and administrative resources needed for successful participation as a Clinical Site in the 

PFDN; and that their participation would be advantageous to the successful attainment of the 

Network's scientific goals and 2) to present a concept application for potential conduct by the 

PFDN. The broad, long-term objectives of their concept application are 1) to compare 

sacrospinous ligament fixation (SSLF) to uterosacral vaginal vault fixation (USWS) and 2) to 

assess the role of perioperative pelvic floor physiotherapy (PFPT) in women undergoing 

transvaginal surgery for apical or uterine POP. Their Specific aims are to: 1) compare the 

anatomic outcomes of SSLF to USWS in women undergoing transvaginal surgery for Stage 2-4 

POP involving the vaginal apex or uterus 3 years after surgery;2) compare functional, sexual, 

and health-related quality of life (HRQOL) outcomes of SSLF to USWS in the same women 3 
Page 88 of 103

years after surgery; 3) assess whether short-term functional, sexual, and HRQOL outcomes 

improve in women receiving PFPT perioperatively compared to those who receive surgery alone; 

4) assess whether perioperative PFPT improves anatomic, functional, sexual and HRQOL 

outcomes 3 years after surgery (long-term) compared to surgery alone and 5) determine the 

incremental cost-effectiveness of perioperative PFPT at the time of transvaginal surgery for POP. 

They present a collaborative multi-centered randomized trial comparing SSLF to USSVS with or 

without perioperative PFPT using a 2x2 factorial study design. A standardized common protocol 

for enrollment, treatment and data collection will be employed by 6-8 Clinical Sites within the 

PFDN coordinated by the data coordinating center.

5 K24 HD060687-02

Midcareer investigator award in patient oriented research

Barnhart, Kurt T

University of Pennsylvania, Philadelphia, PA

$187,466

The recruitment and retention of productive junior investigators is one of the more critical 

priorities of academic medical Institutions and the research community In general. The purpose 

of this Midcareer Investigator Award In Patient-Oriented Research is to provide support for Kurt 

Barnhart MD, MSCE, a reproductive endocrinologist and epidemiologist at the University of 

Pennsylvania. Dr. Barnhart is an accomplished clinical investigator with continuous NIH support 

since he has joined the faculty at Penn in 1996. He has also been recognized as an outstanding 

mentor. The candidate's immediate and long-term career goals center on his desire and intention 

to continue to evolve and mature as a patient-oriented researcher, teacher, and mentor. In doing 

so, he needs to be able to enhance and focus his efforts on conducting patient- oriented research 

(POR), and building a clear training and mentoring path for those interested in POR in women's 

health. This award will be essential to allow him to achieve these goals by protecting 50% of his 

time by reducing his clinical and administrative duties. He will also reduce effort on some of his 

funded projects while concomitantly increasing the effort of junior faculty he currently mentors. 

Mentoring: Dr. Barnhart will focus his mentoring on scholars enrolled in the Masters of Science 

in Clinical Epidemiology (MSCE) via the NIH supported T32 Reproductive Epidemiology 

training grant. Candidates for this program include fellows in sub-specialties in women's health, 

family medicine and/or pediatrics. Other mentees will include junior faculty, and fellows in 

Reproductive Endocrinology and Infertility. He plans to serve as primary thesis mentor for some, 

a research mentor for others, and will transition to become PI of the T32 training grant. Research 

Plan: New science proposed in this application will evaluate the short term and long term 

consequences of assisted reproductive technology (ART), a priory area of research for the NIH. 

In a series of three specific aims he will investigate the association of ART with short term 

perinatal morbidity and childhood development. These three aims were chosen for the ability to 

adequately design and conduct the study in a reasonable period of time, each with a specific 

hypothesis that would lead to important information. Complementary, diverse, and sophisticated 

research methods have been proposed to address this important research area, with focus on 

overcoming inherent limitations in imperfect datasets and potential bias in nonrandomized 

studies. SA#1 will use the national SART database to test if a fresh embryo transfer is associated 

with increased adverse outcome compared to frozen embryo transfer. Aim #2 is use a three arm 

cohort study assessing childhood development in children conceived with IVF, superovulation or 

without medical assistance. SA #3 will use a large administrative dataset to link mothers and 
Page 89 of 103

children and assess for autistic spectrum disorder in true population setting. These aims are 

designed to advance the skills of the PI, enhance multidisciplinary research and provide optimal 

opportunity for mentorship. Finally these aims will likely provide evidence to be used to design 

larger trials, hopefully using the growing cadre of reproductive epidemiologists and POR 

researchers in women's health nationwide, many of whom will have been mentored by Dr 

Barnhart.

5 U10 HD041250-10

The Pelvic Floor Disorders Network

Brubaker, Linda

Loyola University, Chicago, IL

$25,000

Loyola is a productive, innovative clinical research institution that has contributed to the first 

cycle of the Pelvic Floor Disorders Network and they are eager to build on the PFDN's excellent 

start. Their application documents: I. The Qualifications and Commitment of Institution and Key 

Personnel at Loyola A qualified and committed institution with a multidisciplinary faculty with 

experience in clinical trials design and conduct. A highly qualified and committed research team 

Lead by the same PI, Dr. Brubaker, this research team contains urogynecologists and urologists. 

Two of the faculty members received Master's Degrees in Clinical Research Design and 

Statistical Analysis and one is currently in this degree program. A cadre of study coordinators are 

cross-trained to meet the needs of the PFDN study roster. The team has a excellent collaborations 

within the Loyola faculty. II. Loyola's Participation in PFDN Protocols and Procedures High 

quality participation in PFDN protocols with excellent and consistent recruitment. They also 

demonstrate their consistent contributions in PFDN work, including dissemination of PFDN 

scientific findings. Loyola has been productive and has worked well with the PFDN team. Their 

first cycle application proposed the essence of the CARE trial, which was completed ahead of 

schedule and is under consideration for publication. III. A Feasible, Scientifically Relevant 

Concept Protocol (Randomized Surgical Trial): They believe they have demonstrated their 

ability to design and conduct high quality clinical trials. This application also describes a 

randomized surgical trial for women who select vaginal apical reconstruction. A comparison of 

the two most common techniques may inform a future study which seeks to determine which 

route of surgery (abdominal vs. vaginal) is best suited for an individual woman. This trial is a 

feasible, scientifically relevant randomized surgical trial. The draft protocol is suitable for PFDN 

Steering Committee discussion and revision, prior to implementation.

5 P01 HD057877-02

UTERINE Leiomyoma Res Ctr

Bulun, Serdar E.

Northwestern University, Chicago, IL

$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) 
Page 90 of 103

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. 

5 R01 HD061821-02

Identification of Genes Predisposing to Pelvic Floor Disorders

Cannon Albright, Lisa A.

University of Utah, Salt Lake City, UT

$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 genome-
Page 91 of 103

wide 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. 

1 R01 HD061541-01A1

Cellular Mechanisms of Amniotic Fluid Volume Regulation

Cheung, Cecelia, Ph.D.

Oregon Health and Science University, Portland, OR

$200,000

The proposed studies will generate a new level of understanding for the mechanisms of amniotic 

fluid volume regulation. This knowledge is crucial in the development of therapies for the 

treatment of pregnancy complications due to abnormalities in amniotic fluid volume. The studies 

will ultimately lead to improvement in the clinical management of oligohydramnios and 

polyhydramnios, thereby reducing perinatal and neonatal morbidity. A normal volume of 

amniotic fluid (AF) is essential for normal fetal development with favorable perinatal outcome. 

However the mechanisms that regulate AF volume and the factors that maintain the volume 

within the physiological range are not well understood. The current understanding suggests that 

the transfer of AF water and solutes across the fetal membranes into fetal blood vessels that 

vascularize the surface of the placenta is the pathway where regulation occurs. This 

intramembranous (IM) pathway for AF absorption is constituted by an active bulk transport 

component and a passive diffusional component. In addition, the active process is regulated by 

stimulatory and inhibitory factors in the AF and amniotic membrane. Although the existence of 

these regulatory factors has been proposed, their identity and mechanisms of action are not 

known. In this application, they propose to elucidate the cellular pathways of IM transport and 

decipher the factors that regulate these pathways. These studies will be carried out in ovine 

amnion cells in vitro and chronically catheterized ovine fetuses in vivo. In Specific Aim 1, they 

will identify the cellular pathway for transport of solutes across amnion cells and test the 

hypothesis that AF transport is a vesicular transcytotic process via caveolae. They will 

investigate the role of VEGF165 as a stimulator and VEGF165b as an inhibitor of caveolar 

transport, as well as the effect of the soluble VEGF receptor 1 (sVEGFR-1) in antagonizing 

VEGF bioactivity. Specific Aim 2 will determine VEGF165 and VEGF165b mRNA and protein 

levels in amnion cells and amniotic membranes under conditions of normal, increased or 

decreased IM absorption rates. The correlation of VEGF165 levels with sVEGFR-1 will be 

determined. In Specific Aim 3, they will examine the VEGF165 activation of caveolar 

transcytosis by induction of VEGF receptor 2 to initiate a c-Src signaling pathway leading to 

downstream activation of cavoelin-1 and dynamin-2 as required for caveolar endocytosis and 

transcytosis. The involvement of other signaling proteins including protein kinase C and 
Page 92 of 103

phosphatidylinositol 3-kinase will be explored. Specific Aim 4 will investigate the expression of 

the water channel proteins aquaporin 1, 3 and 9 in amnion cells and determine their effects on 

passive and active transport across amnion cells. In Specific Aim 5, they will evaluate the in vivo 

function of the stimulator VEGF165 and the inhibitors VEGF165b and sVEGFR-1 in modulating 

IM absorption rate in ovine fetuses under conditions of normal, increased or decreased AF 

volume. They anticipate the in vivo results to support the in vitro findings that VEGF165 is an 

important determinant of IM absorption and that its stimulatory effect is antagonized by 

VEGF165b and sVEGFR-1. Overall these studies will elucidate the transcellular vesicular 

pathway for AF transport and determine the stimulatory and inhibitory regulatory factors that 

modulate this pathway in amnion cells. Further, the signal transduction cascades that mediate 

these transport events will be investigated. The findings will lead to an improved understanding 

of the etiology of amniotic fluid volume abnormalities. 

1 S06 GM092238-01

Oklahoma Native American Research Centers for Health (ONARCH VI)

Grim, Gloria Ann

Cherokee Nation, Tahlequah, OK

$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

Jumping Eagle, Sara

Oglala Lakota Oyate, Pine Ridge, SD

$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 
Page 93 of 103

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.

1 R01 HD064402-01

Xenograft Study on Growth-Control of Human Uterine Leiomyomata

Kurita, Takeshi

Northwestern University, Chicago, IL

$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 

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. 
Page 94 of 103

5 R01 HD061811-02

Comprehensive Evaluation of Prolapse Meshes by an Interdisciplinary Research Team

Moalli, Pamela A.

Magee-Womens Research Institute, Pittsburgh, PA

$66,667

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 

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 
Page 95 of 103

associated with certain materials. Indeed, the development of such a group is imperative for 

protecting the health of women. 

1 R01 HD060530-01A1

Genetic Studies of Uterine Leiomyomata

Morton, Cynthia Casson

Brigham and Women's Hospital, Boston, MA

$83,333

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 

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. 
Page 96 of 103

5 U10 HD054214-05

Pelvic Floor Disorders Network

Nager, Charles William

University of California San Diego, La Jolla, CA

$25,000

Memory is a critical element of human existence. Consequently, memory loss through 

neurological disease, such as Alzheimer's, or head trauma, severely impacts quality of life. Their 

work will provide a fundamental understanding of the cellular, molecular and neural circuit 

processes of memory providing potential avenues for mnemonic therapy in humans. Memory is 

a fundamental element of human life yet it remains one of the greatest mysteries of modern 

biological research. Memory loss through neurological disease, such as Alzheimer's, or head 

trauma, has a devastating impact on the quality of life. Understanding the molecular process of 

memory would therefore provide potential avenues for mnemonic therapy. The long- term goal 

of this proposal is to understand how memories are formed, consolidated and retrieved at the 

molecular, cellular and neural network level. They use the fruit fly Drosophila as their model 

system because it can learn, it has a relatively simple brain and it is amenable to a sophisticated 

genetic approach. They will use the most up-to-date technology available with a new appetitive 

long-term memory assay to investigate how conserved signaling molecules function within the 

context of defined neural circuits to encode memory. They expect that these studies will have a 

major impact on strategies for human mnemonic therapy. 

5 R01 HD061787-02

Wireless Remote Abdominal Pressure System: Developing a More Comprehensive Unders

Nygaard, Ingrid E.

University of Utah, Salt Lake City, UT

$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 
Page 97 of 103

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 selfadministered 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. 

5 U10 HD054136-05

Utah Pelvic Floor Disorders Network

Nygaard, Ingrid E.

University of Utah, Salt Lake City, UT

$25,000

Pelvic floor disorders are common, bothersome, and inadequately treated. The overarching aim 

of the investigators from the proposed University of Utah Pelvic Floor Disorders Clinical Site is 

to improve women's health in the area of pelvic floor dysfunction. To this end, site specific aims 

include: 1) Identifying priority areas of research, 2) Developing assessment tools, 3) Developing 

and implementing PFDN protocols, 4) Recruiting and enrolling subjects in PFDN protocols, 5) 

Achieving on-target recruitment goals and high subject retention, 6) Ensuring high-quality data, 

7) Transmitting data accurately to the Data Coordinating Center, 8) Participating in data analysis, 

9) Disseminating results to the research community, and 10) Producing high-quality 

publications. The broad scientific aim for the randomized clinical trial outlined in this proposal is 

to evaluate whether post- operative pelvic floor muscle training following surgery for pelvic 

organ prolapse and/or stress urinary incontinence improves post-operative outcomes (anatomic, 

symptomatic and quality of life outcomes) at 3 months, 1 year and 2 years post-operatively.

1 U01 HD063036-01

Racial disparity in adverse pregnancy outcomes: Ancillary study to Nulliparous Pregnancy 

Outcomes Study: Monitoring Mothers-to-Be (NuMoM2b)

Parker, Corette B

Research Triangle Institute, Research Triangle Park, NC

$100,000

The incidence of preterm birth is unequally distributed among races and ethnic groups. For 

example, African-Americans have the highest rate of preterm birth, followed by MexicanAmericans, Asians, and Caucasians. Strikingly, a substantial health disparity exists between 

African-Americans and Caucasians, with African-Americans being 1.6 times more likely to 

deliver preterm infants than Caucasians. In addition, the United States’ high infant mortality rate 

compared to that of Europe is mainly due to the higher frequency of preterm births in the United 
Page 98 of 103

States. The NuMoM2b project is a prospective cohort study of a 

racially/ethnically/geographically diverse population of 10,000 nulliparous women with 

singleton gestations. The women will undergo intensive research assessments during the course 

of their pregnancies to study the mechanisms for and prediction of adverse pregnancy outcomes 

such as preterm birth, preeclampsia, and fetal growth restriction in their first pregnancy. With 

funding from ORWH, biomarkers reflecting the maternal-placental-fetal endocrine milieu related 

to stress will be analyzed from the bio-specimens being collected from 10,000 women. As part 

of the parent study, various questionnaires assessing psychosocial status during pregnancy are 

being administered during pregnancy . The combination of race/ethnic-specific profiles of 

genetic variation, perceived stress and resilience factors (psychosocial environment) as well as 

biomarker differences will likely account, in part, for racial/ethnic disparities in the risk of 

preterm birth. 

1 U01 HD063036-01

The role of maternal nutrition in adverse pregnancy outcomes: Ancillary study to Nulliparous 

Pregnancy Outcomes Study: Monitoring Mothers-to-Be (NuMoM2b)

Parker, Corette B

Research Triangle Institute, Research Triangle Park, NC

$100,000

Preterm birth affects 1 in 8 women in the US, with half a million preterm births each year. 

Excluding congenital malformations, preterm birth accounts for approximately 70 percent of all 

neonatal deaths and nearly 50 percent of long-term neurological problems. Despite decades of 

research, there has been little progress in developing effective interventions to prevent preterm 

birth in the first pregnancy. The NuMoM2b project is a prospective cohort study of a 

racially/ethnically/geographically diverse population of 10,000 nulliparous women with 

singleton gestations. Nutrition is an understudied area with relation to preterm birth, although 

several nutritional factors have been related to preterm birth. There is biologic plausibility for the 

relationship of folate and vitamin B12 with preterm birth, as both may be important regulators of 

pro-inflammatory cytokine and DNA synthesis. Vitamin D is another example of a nutritional 

factor that, if deficient, has been linked to adverse pregnancy outcomes, including preterm birth, 

preeclampsia, and fetal growth restriction. With funding from ORWH, the role of nutrition in 

adverse pregnancy outcomes will be studied by administering the Modified Block 2005 Food 

Frequency Questionnaire in all 10,000 women in the cohort. A full assessment of usual intake of 

over 51 nutrients and 7 food groups in the 3 months before conception will be conducted by 14 

weeks of gestation using a semi-quantitative modified Block 2005 food frequency questionnaire 

and findings will be correlated to clinical data and biospecimen collection as part of the parent 

study to determine the role of maternal nutrient status in adverse pregnancy outcomes.

5 U10 HD041261-10

Perioperative Pelvic Floor Rehab: A Randomized Trial

Richter, Holly E

University of Alabama At Birmingham, Birmingham, AL

$25,000

Surgical techniques for the treatment of stress incontinence (SUI) have significantly evolved 

over the last 100 years. The gold standard Burch urethropexy and pubovaginal sling procedures 

are now being performed less frequently, with the increased use of the newer minimally invasive 
Page 99 of 103

mid-urethral sling procedures, the most common being the tension-free vaginal tape procedure 

(TVT). The TVT procedure is comparable in efficacy to the open Burch procedure with low 

morbidity and fewer complications. Because the sling is placed at the level of the mid-urethra 

under no tension, it was thought that the TVT would yield fewer postoperative lower urinary 

tract symptoms. However, a review of the literature has not borne this out, with postoperative 

storage symptoms reported in up to 42% of women. The primary purpose of the proposed 

randomized clinical trial is to test whether a perioperative behavioral/pelvic floor muscle training 

program can reduce the occurrence of these postoperative storage symptoms and voiding 

dysfunction in women undergoing a TVT procedure for SUI. Behavioral interventions are known 

to be effective for treating urge incontinence and voiding dysfunction unrelated to surgery, but 

have not been tested as a preventive adjunctive strategy. Approximately 400 subjects will be 

randomized to a perioperative behavioral program or usual care. The intervention will be 

implemented 2 weeks preoperatively, and reinforced before leaving the hospital and two weeks 

postoperatively. The primary outcome will be complaints of urgency, frequency, nocturia and 

urge incontinence using the overactive bladder questionnaire (OABq). Evaluations will be 

performed at 2 and 6 weeks, 3, 6, and 12 months postop, and will include the OABq, 

questionnaire for urinary diagnosis (QUID), urogenital distress inventory (UDI), pelvic organ 

prolapse/urinary incontinence sexual function questionnaire (PISQ), patient global impression of 

severity (PGI-S) and SF-36. Subjects will also complete a 7-day bladder diary to assess 

frequency of storage symptoms. Secondary aims are to determine whether this intervention 

reduces time to voiding and symptoms of voiding dysfunction, whether it impacts on patient 

satisfaction and quality of life, and to identify predictors of postoperative storage symptoms and 

voiding dysfunction symptoms. This type of information will allow physicians to more 

effectively counsel and treat their incontinent female patients to further enhance long-term 

quality of life.

5 U10 HD054241-05

Nichd Pelvic Floor Disorders Network

Schaffer, Joseph I

University of Texas Southwest Medical Center, Dallas, TX

$25,000

This application describes the qualifications and experience of the urogynecology and urology 

faculty and research teams at the University of Texas Southwestern (UT Southwestern) Medical 

Center and Parkland Hospital and the facilities and patient population available to carry out 

clinical protocols sponsored by the Pelvic Floor Disorders Network. In 2004, there were more 

than 2,100 women with pelvic floor disorders seen in their clinics and 617 women underwent 

surgical procedures for correction of pelvic floor disorders. The Departments of Obstetrics and 

Gynecology and Urology have increasingly collaborated since 1997 to offer comprehensive care 

of women with pelvic floor disorders. In addition to urogynecology and urology, collaboration 

includes faculty from colorectal surgery, radiology, physical therapy, and maternal-fetal 

medicine. The clinical research teams described in this application have successful prior as well 

as on-going experience in NIH sponsored national multi-center trials. Centerpieces in this 

application are two existing research clinics, one targeted at private patients (operated by the 

Urology Department) and the other focused on medically indigent patients (operated by the 

Obstetrics and Gynecology Department). Also included in this application is a concept 

application for a randomized trial designed to assess the efficacy of end-to-end versus 
Page 100 of 103

overlapping repair of the external anal sphincter lacerated during childbirth. The primary 

outcome is anal incontinence which is a significant consequence of such lacerations. This trial 

would permit accurate evaluation of the outcome of specific surgical procedures which is one of 

the prime areas of interest leading to creation of the Pelvic Floor Disorders Network. They are of 

the view that along with strategies for prevention of anal sphincter laceration during childbirth, 

optimal management of the torn sphincter should also be studied since more than 200,000 

women sustain such pelvic floor injuries each year in the United States.

Z01 HD008737-10

ORWH-NICHD Leiomyoma Tissue Bank

Segars, James

NICHD Intramural program, Bethesda, MD

$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 

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.

5 U01 HD041249-10

Pelvic Floor Disorders Network-Data Coordinating Center

Spino, Catherine A

University of Michigan, Ann Arbor, MI

$25,000

Pelvic floor disorders, such as urinary incontinence, pelvic organ prolapse, and fecal 

incontinence, are common and significant health-related problems for women in the United 

States. Outcomes following surgical and non-surgical intervention for pelvic floor disorders have 

not been adequately evaluated. As a result, data necessary to fully inform patients and to make 

important policy decisions are unavailable. The long-term objective of the Pelvic Floor Disorders 

Network (PFDN) is to systematically evaluate these outcomes. This application to be the Data 

Coordinating Center (DCC) for the pelvic floor disorders network brings together experienced 

investigators from biostatistics, urogynecology, urology, quality of life and health services 

research to prospectively assess the outcomes from various surgical interventions for female 

pelvic floor disorders. The specific aims of the DCC are to: 1. Assist in protocol development by 

providing expertise in the design, conduct and analysis of clinical trials conducted by the PFDN. 

2. Provide expertise in measurement of quality of life and in the selection of the appropriate 

instruments to assess treatment outcomes and, when appropriate, to perform the interviews. 3. 

Coordinate the implementation of the study protocols approved by the Steering Committee, 

including design of the case report forms and interviewing protocols, development of a manual 
Page 101 of 103

of operations, centralized database management with either centralized or remote data entry, 

submission of an IND to the FDA when necessary, and by organizing training and certification 

sessions, as needed. 4. Establish a database for each study conducted by the PFDN. 5. Implement 

either centralized or web-based data entry and verification. 6. Monitor the clinical sites with 

respect to data quality. 7. Provide infrastructure for monitoring adverse events and regulatory 

oversight for the network. 8. Provide logistical support for the Steering Committee, Advisory 

Board and DSMB, for both face-to-face meetings and teleconferences. 9. Maintain a website for 

the PFDN that includes web pages with content for the public, and a password- protected site 

with all study documentation and databases. 10. Manage and distribute protocol funds to the 

Clinical Centers. To illustrate the work of the DCC, a randomized clinical trial is proposed to 

compare surgical procedures for pelvic organ prolapse using a vaginal approach.

Adrenal hyperplasia among adolescent patients polycystic ovarian syndrome (Bench To Bedside

Program)

Stratakis, Constantine A.

NICHD Intramural, Bethesda, MD

$200,000

Adolescent and young women of reproductive age and clinical picture of polycystic ovarian 

syndrome (PCOS) have increased adrenal androgens. Anecdotal re reports from patients and 

animal studies have also suggested that this phenotype is also associated with adrenal 

hyperplasia. Finally, certain minority populations (i.e. Hispanics, African-Americans) are 

particularly susceptible to PCOS and related complications (e.g. diabetes, infertility). The 

common link between the adrenal and ovarian pathology has been postulated to be insulin 

resistance, but this remains unclear. Dr. Ten runs a large clinic in down-town New York where a 

lot of these patients are being seen. In this proposal, they plan to bring a subset of these patients, 

those that have elevated adrenal steroid hormones, to the NIH Clinical Research Center (NIHCRC) and study their metabolic profile, adrenal imaging and steroidogenesis before and after 

treatment with metformin, an insulin sensitizer, and genetic parameters. This study will clearly 

lead to a new clinical protocol and offer the opportunity to study a new disorder for the pediatric 

endocrine clinical and program.

5 U10 HD041267-11

Pelvic Floor Disorders Network

Visco, Anthony G

Duke University, Durham, NC

$25,000

Women's health research at the University of North Carolina (UNC) is sophisticated and 

widespread with many committed investigators addressing issues of fundamental importance to 

women. UNC 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 Division of 

Urogynecology and Reconstructive Pelvic Surgery. They offer comprehensive evaluation and 

treatment options in a high-volume care setting that serves as a tertiary referral center for women 

from across the state. Women sought consultation or treatment for more than 2700 pelvic floor 

disorders by Urogynecologists at UNC in the previous two years. Seventy-eight percent of the 

women were Caucasion and 15% were African American, predominantly from rural and 

suburban communities with stable care and follow-up patterns. Approximately 427 women had 
Page 102 of 103

multi-channel urodynamic studies annually. UNC providers have extensive expertise in both 

surgical and non-surgical management of urinary incontinence, pelvic organ prolapse and 

defecatory dysfunction. The Division of Urogynecology performs an average of 106 surgical 

procedures for the primary indication of urinary incontinence, 300 for prolapse and provides 

medical management for over 1,464 women with these conditions each year. The UNC Pelvic 

Floor Disorders Research Collaborative, led by the Division of Urogynecology is a 

multidisciplinary team of outstanding investigators in Urogynecology, urology, gastroenterology, 

radiology, maternal-fetal medicine and clinical research methodology. They have a history of 

strong clinical ties and dedication to interdisciplinary research. Diagnostic resources include 

muti-channel urodynamic testing, cystoscopy, defecography, pelvic MRI, 360-degree endoanal 

ultrasound, anal manometry and needle electromyography. Clinical services include surgical 

treatment of complex pelvic floor disorders and a wide range of non-surgical options. As an 

active PFDN clinical network site, UNC has an established research infrastructure with the 

proven ability to support large-scale, multi-centered clinical research. The collaborative is wellequiped and uniquely qualified to continue as a valuable member of the Pelvic Floor Disorders 

Network. Given the exceptional quality of the research opportunities and resources available at 

UNC, the stable and diverse patient population, the strength of the investigator pool, their proven 

high-level recruitment and the commitment of the institution to the stated goals of this RFA, they 

look forward to continuing to make substantial contributions to advancing women's health 

related to pelvic floor disorders.

1 R01 HD65029-01A1

The Genetics of Polycystic Ovary Syndrome

Welt, Corrine, M.D.

Massachusetts General Hospital, Boston, MA

$200,000

Polycystic ovary syndrome (PCOS) is a disorder of irregular menses and elevated androgens that 

carries a high risk for diabetes, hypertension and elevated lipids. The investigators have now 

discovered a genetic variant that is associated with polycystic ovary syndrome in a genome-wide 

association study and will try to determine the causal variant and gene it marks. Discovering the 

variants and/or gene(s) that predispose to PCOS will determine an etiology and will provide a 

novel target to develop new treatments for the 1 in 10 reproductive age women it affects. 

Polycystic ovary syndrome is the most common endocrine disorder in reproductive age women, 

yet its etiology is poorly understood. The disorder is defined by its cardinal features: irregular 

menstrual cycles, hyperandrogenism and a polycystic ovary pattern on ultrasound. In addition, 

women with PCOS have increased risk for infertility, endometrial cancer, type 2 diabetes and 

cardiovascular risk factors. They completed a genome-wide association study in collaboration 

with deCODE in Iceland. The study identified a variant on chromosome 4 reaching genomewide 

significance in an Icelandic case control cohort and replicating in an identically phenotyped 

Boston cohort. The broad goal of this proposal is to identify the causal variant that this risk 

variant marks through fine mapping. They will also examine the functional effects of the causal 

variant using expression studies and/or assays of protein function. Finally, they will examine the 

phenotypic features defined by the genotype. Specific Aim 1 will examine the region around the 

chromosome 4 variant to identify the causal variant that affects protein production or gene 

expression. Fine mapping will be performed using common single nucleotide polymorphisms 

(SNPs) in the HapMap and 1000 genomes projects. In addition, the exons and promoter regions 
Page 103 of 103

of genes in linkage disequilibrium with the associated variant will be sequenced in large numbers 

to identify rare variants that may affect protein production or gene expression. Specific Aim 2 

will dissect the phenotype conferred by the genotype in PCOS, controls, males and 

postmenopausal women using an extensive database assembled by the PI over the past 6 years. 

Specific Aim 3 will examine expression of two candidate genes in LD with the chromosome 4 

variant in carriers and non-carriers to determine the gene of interest. When a causal variant is 

identified, expression will also be examined to identify a functional effect of variant(s) in a 

lymphoblastoid cell line database and in adipose, theca and peripheral white blood cells in vitro 

using quantitative PCR. Coding sequence causal variants and rare variants will be assessed using 

signaling assays and overexpression or knock-down of the variants in cell systems and animal 

models. These studies will uncover the causal variant and gene that is marked by the first known 

variant identified in a genome-wide case control association study of PCOS. The proposal has 

the potential to illuminate the etiology of PCOS. Such information has been long in coming and 

is essential to provide better diagnostic and treatment information for this very common disorder 

with its adverse health consequences.