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Summaries of Co-Funded Research, FY 2012

NIH Office of Research on Women's Health

Office of the Director

Division of Program Coordination, Planning, and Strategic Initiatives

National Institutes of Health
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Contents

National Cancer Institute........................................................................................................................3

National Eye Institute........................................................................................................................... 19

National Heart, Lung, and Blood Institute ..................................................................................... 20

National Institute on Aging................................................................................................................. 27

National Institute on Alcohol Abuse and Alcoholism................................................................ 33

National Institute of Allergy and Infectious Diseases................................................................. 35

National Institute of Arthritis and Musculoskeletal and Skin Diseases................................. 55

National Institute of Biomedical Imaging and Bioengineering................................................ 59

Eunice Kennedy Shriver National Institute of Child Health and Human Development ... 60

National Institute of Diabetes and Digestive and Kidney Diseases........................................ 80

National Institute on Drug Abuse ..................................................................................................... 88

National Institute of Environmental Health Sciences................................................................. 89

National Institute of General Medical Sciences............................................................................ 91

National Institute of General Medical Sciences & Indian Health Service............................ 92

National Institute of Mental Health.................................................................................................. 93

National Institute on Minority Health and Health Disparities.................................................. 97

National Institute of Neurological Disorders and Stroke........................................................... 98

John F. Fogarty International Center for Advanced Study in the Health Sciences..........100

National Center for Complementary and Alternative Medicine ............................................110

 
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National Cancer Institute

Title: Definition of Microenvironment in Breast Cancer

P.I.: Mina Jahan Bissell 

Institution: University of California, Berkeley, Lawrene Berkeley National 

Laboratory 

Grant No.: CA064786-17

Award: $18,750

One of the earliest manifestations of malignant progression is loss of tissue organization. 

This proposal continues to examine the hypothesis that architectural integrity is crucial 

for maintenance of normal breast function as well as for suppression of neoplasia. We 

have postulated that elucidation of a “signaling integration plan” that establishes and 

maintains polarity and structure within the acini and ducts of breast tissue will uncover 

prognostic and therapeutically-relevant markers of intermediary steps in malignancy. As 

such, we postulated and provided evidence that myoepithelial cells (MEPs) provide 

crucial structural and functional cues to luminal epithelial cells (LEPs) partly via 

production of, and signaling through, laminin-111 (Ln-1). We further postulated, and 

now provide additional evidence, that in traditional cell culture conditions, purified LEPs 

almost immediately develop a hybrid LEP/MEP phenotype acquiring aspects of MEP 

gene expression and in particular developing the tumor suppressor functions normally 

conferred in vivo by MEPs and an ability to make acini, which normally requires the 

presence of MEPs. Consequently, in order to make relevant models for the study of 

human LEP-MEP interactions we must identify the conditions that instruct these cell 

types to retain their original functions. Accordingly, we have developed new and versatile 

microenvironmental arrays (MEArrays) to probe how MEPs and LEPs become, and 

remain, determined. We now propose to expand our findings in 3 specific aims. We will 

specifically: 1- identify pathways that allow retention of MEP- and LEP- specific 

functions in culture using designer MEArrays and designer media. We then could probe 

the importance of desmosomal proteins and other regulatory molecules in addition to Ln1 produced by MEPs, in how MEPs and LEPs interact to retain polarity, architecture and 

function. 2- complete the identification of Ln-1 signaling cascade components for 

mammary specific functions using inhibitory peptides, blocking antibodies, mutant cells 

and shRNA ablation in high throughput assays using Cellomics and other devices and 

designer 3D microenvironments. 3- identify and characterize central players and 

connections in the ‘signaling integration plan’ for structural integrity of acini using 

bioinformatics analysis of gene expression arrays, genome-wide methylation profiles and 

other changes in chromatin structure, identification of miRNAs affecting cellular 

architecture, and by positioning the new genes we identified using a unique 3D screen, on 

our integration map. Collectively these experiments address the importance of MEP/LEP 

interactions in maintenance of polar acinar structures in breast tissue, and could also 

provide a proof of principle for other tissues. Since loss of appropriate balance and/or 

integration of these signals leads to malignancy, our results will both advance 
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fundamental knowledge and yield novel markers for early diagnosis and therapeutic 

strategies to limit and/or reverse breast tumor progression. 

Title: P3K, Retroviral Oncogene, and Homolog of PI 3-Kinase

P.I.: Peter K. Vogt 

Institution: Scripps Research Institute 

Grant No.: CA078230-14

Award: $18,750

The goal of this project is to achieve a molecular understanding of the oncogenicity of 

phosphatidylinositol 3-kinase (PI3K). The proposed work will use two basic approaches: 

(1) a genetic analysis of the oncogenic functions of p110¿, the catalytic subunit of PI3K, 

and (2) genome-wide interrogations for novel regulators and targets of PI3K. The genetic 

analysis will concentrate on the interactions between p110¿ and Ras as well as p110¿ and 

p85. These interactions are critical to the oncogenicity of p110¿; they are fundamentally 

changed in the cancer-specific gain-of-function mutants of p110¿. The p110¿ protein 

carrying cancer-specific mutations in the helical domain (E542K, E545K) has 

requirements for p85- and Ras-binding that are opposite to those of the kinase domain 

mutant (H1047R). The helical domain mutants depend on Ras-binding but are largely 

independent of p85-binding. The kinase domain mutant does not require Ras but needs 

p85 to be active. We plan to analyze mutants of p85 and of Ras in which specific 

functions are disabled for their ability to activate wild-type and mutant p110¿. This 

genetic analysis will advance our understanding of the molecular mechanisms by which 

cancer-specific mutations in p110¿ induce a gain-of-function and make the protein 

oncogenic. The genome-wide interrogations for regulators and targets will take advantage 

of two new technologies. (1) A screen of expression libraries in the yeast Saccharomyces 

cerevisiae. This is a lethality screen based on the fact that expression of PI3K is toxic to 

Saccharomyces cerevisiae. The observed growth defect can be rescued by the expression 

of negative regulators of PI3K. Using this screen, we have identified several novel 

suppressors of PI3K. We will characterize these regulators and define the signaling 

chains that connect them to PI3K. (2) The second technology is a kinome screen that uses 

the two universally conserved lysines in ATP pockets of kinases to tag ATP-binding 

proteins by covalent linkage to biotin. We have used this method to reveal PI3K-induced 

changes in the kinome and, during initial studies, have identified three growth-regulatory 

kinases that are differentially expressed in PI3K-transformed cells. The roles of these and 

additional PI3K targets identified by the kinome screen will be analyzed and determined.

Title: Molecular Mechanisms of BRCA1-Dependent DNA Damage 

Response and Tumorigenesis 

P.I.: Xiaochun Yu 

Institution: University of Michigan at Ann Arbor 

Grant No.: CA132755-05S1

Award: $18,750
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BRCA1 is a nuclear polypeptide to suppress familial breast and ovarian cancers. 

Accumulated evidence suggests that BRCA1 participates in DNA damage response. 

However, the molecular mechanisms by which BRCA1 participates in DNA damage 

response remain elusive. Recently, we have identified two new BRCA1 partners, RAP80 

and CCDC98. Both RAP80 and CCDC98 associate with BRCA1 BRCT domain and 

participate in DNA damage response. Functionally, RAP80 and CCDC98 facilitate 

BRCA1’s translocation to DNA damage sites. To search for the signals that recruit this 

BRCA1 complex to the DNA damage lesions, we have found that BRCA1-associated

protein RAP80 recognizes ubiquitinated histone H2A and H2B. And both histone H2A 

and H2B are further ubiquitinated following DNA damage. In addition, we have 

identified two biallelic missense mutations and one truncation mutation of RAP80 gene 

in breast and ovarian cancer cells, suggesting that RAP80 could be another breast and 

ovarian tumors suppressor in BRCA1-dependent pathway. Thus, we hypothesize that 

recognition of ubiquitinated histone by RAP80 is the molecular basis that loads BRCA1 

to DNA damage sites, which regulates proper DNA damage response, protects genomic 

integrity and prevents breast and ovarian tumor development. We propose following 

experiments to examine our hypothesis. Aim1: To examine the molecular mechanism by 

which RAP80 and CCDC98 target BRCA1 to DNA damage lesions. Aim2: To examine 

the functional defects of RAP80 mutations in BRCA1-dependent DNA damage response. 

Aim3: To examine the role of RAP80 in tumor prevention. In summary, studies outlined 

here will not only reveal the molecular mechanism by which BRCA1 participates in 

DNA damage response, but also identify the functional partners of BRCA1 in tumor 

suppression. 

Title: Low-Dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast 

Cancer Risk Reduction

P.I.: Melanie R. Palomares 

Institution: Beckman Research Institute of City of Hope

Grant No.: CA140245-03

Award: $18,750

Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk 

Reduction Mantle radiation has been a cornerstone of HL treatment; however, female 

survivors of HL treated with mantle irradiation before age 30 have a 20- to 55-fold 

increased risk of developing breast cancer (BC)—a risk that is comparable to that of 

BRCA mutation carrierrs. Surgical prophylaxis is very effective in reducing the risk of 

BC, but such invasive strategies are not suitable for all women. Pharmacologic 

interventions exist, but only tamoxifen is approved for use in young women who have not 

yet reached menopause. Standard-dose tamoxifen (20 mg daily) is associated with 

undesirable side effects, but recent studies have laid convincing groundwork that 

tamoxifen at lower doses may be similarly efficacious in reducing BC risk with fewer 

side effects. We hypothesize that tamoxifen administered at a lower dose (5 mg daily) 

would be both an efficacious and safe non-surgical risk reduction intervention for female 

adult survivors of HL diagnosed during childhood or as a young adult. Thus, using a 

Phase IIb randomized, double-blind, placebo-controlled trial of low-dose tamoxifen (5 
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mg daily) in long-term female HL survivors treated with chest radiation, we aim to 1) 

Determine the impact of a two-year course of low-dose tamoxifen on well-established 

surrogate biomarkers of chemopreventive efficacy; 2) Establish the safety and tolerability 

of low-dose tamoxifen in this population; and, as an exploratory aim, 3) Examine the 

modifying effect of several well-defined demographic and clinical characteristics 

associated with radiation-related BC risk on the risk:benefit ratio from this intervention. 

Eligible subjects who provide informed consent will be randomized to 5 mg per day of 

tamoxifen versus placebo for two years. Outcomes will include several surrogate 

biomarkers of efficacy, including mammographic breast density (MBD, primary 

endpoint), breast cytomorphologic and proliferation measures, and insulin growth factors. 

Subjects will be carefully followed for safety and tolerability using patient-reported 

outcomes as well as lipid profiles, clotting factors, and markers of bone turnover as 

objective endpoints. Risk modifiers that will be examined include age, menopausal status, 

prior hormone use, body mass index, personal history of benign breast disease, and 

family history of cancer, as well as chest radiation dose, age at exposure, and latency 

from chest radiation. A sample size of 127 per arm will be able to detect a 20% reduction 

in MBD with low-dose tamoxifen relative to placebo with 80% power. We have 

identified over 900 potentially eligible subjects within our consortium of five institutions 

that have well-developed infrastructure to follow childhood cancer survivors long-term, 

thus demonstrating that we will have a sufficiently sized pool to draw the eligible patient 

population from and complete the study. At completion of this study, we hope to identify 

a well-tolerated risk reduction option for HL survivors that are at high risk for developing 

BC. Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk 

Reduction Public Health Relevance: Survival from Hodgkin lymphoma (HL) is excellent, 

but chest radiotherapy (RT) has been a cornerstone of treatment, and women with HL 

exposed to chest RT when they are young have a 20- to 55-fold increased risk of 

developing breast cancer (BC). Tamoxifen reduces the risk of BC by 50%, but at the cost 

of some undesirable side effects, while more recent studies suggest that lower dose 

tamoxifen may be similarly efficacious in reducing BC risk with fewer side effects. We 

believe that tamoxifen administered at 5 mg daily would be an ideal non-surgical risk 

reduction intervention for female HL survivors exposed to chest RT at high risk for BC; 

therefore, we plan to test this hypothesis in a Phase IIb clinical trial. 

Title: PET-MRI for Assessing Treatment Response in Breast Cancer 

Clinical Trials

P.I.: Thomas E. Yankeelov 

Institution: Vanderbilt University Medical Center 

Grant No.: CA142565-03S1

Award: $18,750

We propose to develop integrated high field (3T) magnetic resonance imaging (MRI) and 

positron emission tomography (PET) methods for assessing the effects of molecularly 

targeted anti-angiogenesis and cytoxic treatments in breast cancer clinical trials. Our goal 

is to provide the breast cancer community with practical data acquisition and analysis 

protocols that facilitate the translation of advanced imaging technologies into patient 
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management and clinical trials. Dynamic contrast enhanced MRI (DCE-MRI) and 

diffusion weighted MRI (DW-MRI) can report on vascular status, tissue volume 

fractions, and cellularity, while fluorodeoxythymidine PET (FLT-PET) can report on cell 

proliferation. We propose to combine these MRI and PET data to provide anatomical, 

physiological, and molecular assessments of the response of breast tumors to novel antiangiogenic and cytoxic treatments in clinical trials. To accomplish these goals we will 

pursue the following specific aims: 1. We will develop high field breast MRI protocols 

that measure tissue cellularity and vascularity. We will then develop methods for the 

rigorous registration of these MRI measures with quantitative PET characterization of 

cell proliferation. We will develop the algorithms and software architecture necessary for 

synthesizing the imaging data with (traditional) clinical data to assisting in clinical 

decision making. 2. In an ongoing Phase II study we will employ DCE-MRI, DW-MRI, 

and FLT-PET to assess the degree of tumor response after one and two cycles of 

Carboplatin and nab-Paclitaxel with or without Vorinostat in HER2-negative primary 

operable breast cancer. 3. In our planned Phase II study we will employ DCE-MRI, DWMRI, and FLT-PET to assess the degree of tumor response after one and two cycles of 

neoadjuvant cisplatin, paclitaxel and the TOI inhibitor everolimus in patients with triple 

negative breast tumors. As the anti-cancer agents employed in these clinical trials are 

implicated in apoptosis and/or inhibition of cellular proliferation and/or inhibition of 

angiogenesis, we hypothesize that changes in metrics of cellular proliferation and 

vascularity, when merged with traditional clinical biomarkers, will provide significantly 

more accurate predictions on patient response than traditional methods of tumor response 

including RECIST. RELEVANCE: We propose to develop integrated magnetic 

resonance imaging (MRI) and positron emission tomography (PET) methods for 

assessing the effects of molecularly targeted treatments in breast cancer clinical trials. We 

hypothesize that the synthesis of imaging metrics reporting on vascularity, cellularity, 

and cell proliferation will provide predictive measurements of tumor response to 

treatment in appropriately selected clinical trials. Our goal is to provide the breast cancer 

community with practical data acquisition and analysis protocols that facilitate the 

translation of advanced imaging technologies into patient management and clinical trials. 

Title: Understanding and Preventing Breast Cancer Disparties in 

Latinas

P.I.: Beti Thompson 

Institution: Fred Hutchinson Cancer Research Center 

Grant No.: CA148143-03

Award: $18,750

Breast cancer is the most common cancer among Hispanic women in the United States 

(US). The incidence of breast cancer among Hispanics (83.5 per 100,000) is lower than 

that among non-Hispanic Whites (147.3 per 100,000); however, as Hispanic women 

adopt the practices of mainstream US culture, their risk for breast cancer increases. 

Further, Hispanic women are at increased risk for breast cancers with poor prognosis. 

The overarching theme of this PSO application is to understand and prevent pre-cursors 

of breast cancer and to reduce breast cancer morbidity and mortality among Latinas. This 
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will be done at multiple levels and will engage researchers across several disciplines. 

Projects have been carefully designed to contribute understanding to and preventing 

breast cancer in Latinas. It is the lonq-term goal of this PSO application to understand the 

antecedents of breast cancer in the Latina population, to understand the types of breast 

cancer found in the Latina population, and develop and implement a comprehensive 

program of screening to increase the opportunities for early breast cancer detection 

among Latinas. Our short-term obiectives are to: 1. Increase breast cancer screening 

among age-eligible Latinas; 2. Understand the processes by which ancestry, BMI, 

inflammation, and breast cancer are related in Latinas 3. To understand aspects of the 

etiology of poor prognosis breast cancers by identifying risk factors related to triple 

negative (TN) and HER-2-overexpressing (H2E) tumors, which are more commonly 

found in Latinas compared to non-Hispanic whites 4. To understand the role of ancestry 

in breast cancer antecedents and incidence among Latinas. 5. To explore expression of 

genes involved in tumor-related pathways signaling. This application is committed to a 

comprehensive multi-level approach to reducing health disparities. Its projects range 

from the biologic and genetic to the social context within which people live. Through its 

four projects and cores, the proposed Center will cover a myriad of aspects of breast 

cancer, from biological processes and genetic pathways to individual determinants and 

social determinants of breast cancer. 

Title: Assisted Reproductive Technology and Risk of Childhood Cancer

P.I.: Barbara Joan Luke 

Institution: Michigan State University 

Grant No.: CA151973-02

Award: $18,750

Use of assisted reproductive technology (ART) has risen steadily in the United States 

during the past two decades due to several reasons, including childbearing at older 

maternal ages and increasing insurance coverage. Studies have reported significantly 

higher risks of adverse perinatal outcomes in assisted—versus spontaneous—conception

pregnancies, including an excess of prematurity, low birthweight, and birth defects. ART 

and/or infertility may influence the incidence of other conditions with prenatal origins, 

such as childhood cancer. In addition, the prevalence of imprinting disorders such as 

Beckwith-Wiedemann and Angelman syndromes is elevated among children conceived 

by ART; some of these disorders, in turn, drastically raise the risk of several embryonal 

cancers that occur in early childhood. Several cohort, case-control, and case-series studies 

of assisted reproduction and childhood cancer have reported null results, although all 

were limited by small sample size and could not differentiate specific cancer types. One 

study that focused specifically on hepatoblastoma found that use of infertility treatment 

or assisted reproduction was associated with a nine-fold increased risk of disease. Using 

the resources of the Society for Assisted Reproductive Technology (SART) and the birth 

and cancer registries in 20 States and New York City, we propose to conduct the largest 

study to date of ART and childhood cancer risk. SART maintains an ongoing national 

database of programs that provide ART services in the United States as mandated by the 

federal Fertility Success Rate and Certification Act of 1992 [PL 102-493]. As of 2006, 
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the latest year of data available, this included comprehensive data (including identifiers 

sufficient for linkage) on 138,198 ART cycles from 483 clinics resulting in 41,343 

pregnancies and 54,656 infants for a single year. We propose to link the data from the 

SART database from 2004-2013 to the birth and cancer registries of 20 states and New 

York City, including the five states with the highest numbers of ART births (California, 

New York, Illinois, New Jersey, and Massachusetts), to create a cohort of approximately 

30 million children, including over 467,000 conceived by ART to evaluate the 

association between assisted reproduction and the risk for childhood cancer. The specific 

aim of this study is to compare the incidence of childhood cancer in children with 

assisted conception to that in the general population. 

Title: Feasibility of Community-Based Tampon Self-Sampling To 

Prevent Cervical Cancer

P.I.: Elizabeth H. Fontham 

Institution: Louisiana State University Health Sciences Center New Orleans

Grant No.: CA157263-01A1

Award: $200,000

Medically underserved women are generally at higher risk for many health problems 

including cervical cancer. Solutions can often be found by utilizing resources within the 

community. An academic-community partnership has been formed to develop a novel 

approach to screening for cervical cancer. High risk types of human papillomavirus 

(HPV), 16, 18 and others, are etiologically linked to cervical cancer. HPV can be detected 

from samples obtained from self-swabbing of the vagina, urine testing, or insertion of 

tampons. These methods could be performed in the community or at home by women, 

which is useful for the group of women not visiting the gynecologist to receive 

recommended testing. This study will compare the effectiveness of home-based self 

sampling screening for cervical cancer with conventional Pap testing in a communitybased setting. Given the ease of home use, it is hypothesized that home-based tampon 

testing for HPV DNA will be equal or superior to the annual Pap testing. For such home 

sampling to be effective, it must be: (1) used at least as much as current referral rates to 

the gynecologist; (2) acceptable to the woman as a means to prevent cervical cancer; (3) 

able to be performed at home; and (4) able to identify those women at risk for developing 

cervical cancer. The specific aims of this project are to: compare compliance with a 

home-sampling tampon HPV test to compliance with clinic Pap testing; assess a high risk 

population’s acceptance of home use of a tampon for HPV testing in general and 

compared to traditional clinically administered Pap testing; assess a high risk 

population’s ability to correctly follow instructions for home tampon sampling for HPV 

testing; and assess the accuracy of the home administered tampon HPV results. In order 

to achieve these aims, a group of women will be asked to administer the tampon sampling 

at home and return via mail. Another group will have conventional Pap testing for 

comparison. Surveys of satisfaction will also be conducted. 
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Title: Roles of EGFR and miR-143/miR-145 in Western Diet-Promoted 

Colonic Tumorigenesis

P.I.: Bruce Marc Bissonnette 

Institution: University of Chicago 

Grant No.: CA164124-01A1

Award: $150,000

While Western diets are implicated in increased colon cancer risk, molecular 

underpinnings of these dietary effects remain largely unknown. The azoxymethane 

(AOM) and Apc+/min mouse models mimic many features of human colon cancer, 

including tumor promotion by Western diet. We showed that Western diet up-regulated 

ligands for epidermal growth factor receptors (EGFR). Furthermore, EGFR was required 

for tumor promotion. Several EGFR ligands are released from membrane-bound proligands by the lipid-raft-associated metalloproteinase ADAM17. Our recent studies 

indicate that ADAM17 is down-regulated by microRNA-145 (miR-145), whereas K-ras, 

an EGFR effector is suppressed by miR-143. These co-transcribed miRNAs are downregulated in human colon cancer. We recently showed that EGFR signals downregulate 

miR-143 and miR-145 in AOM and Apc+/min tumors. Furthermore, these miRNA 

reductions are necessary for EGFR mitogenic effects. Based on our data we hypothesize 

that ADAM17 up-regulation and miR-143 and miR-145 down-regulation play essential 

roles in Western diet-induced tumor promotion. We propose several aims to address this 

hypothesis: Aim 1: Elucidate the requirement for ADAM17 in diet-promoted colonic 

tumorigenesis. We hypothesize that ADAM17 inhibition or deletion will suppress dietrelated tumor promotion. We will use 1a) the AOM model in conditional ADAM17-

deleted mice; 1b) the Apc+/min model with a novel ADAM17 pharmacological inhibitor 

INCB3619 to dissect the role of ADAM17 in diet-promoted tumorigenesis; 1c) in vitro 

studies of lipid rafts to dissect fatty acid effects on ADAM17 in colon cancer cells. Aim 

2: To determine contributions of miR-143 and miR-145 in diet-promoted colonic 

tumorigenesis. We hypothesize that loss of these miRNAs is necessary for diet-induced 

tumor promotion. We will employ Apc+/min mouse interbred with 2a) transgenic mice 

expressing villin-promoter regulated pre-miR-143 and pre-miR-145; or with 2b) miR-143 

null mice or with 2c) miR-145 null mice to uncover the role of these miRNAs in dietpromoted tumorigenesis. In aim 2d), we will examine other miRNAs implicated in 

ADAM17 regulation and/or diet-related tumorigenesis, including miR-1, -31, -148, and -

152. Aim 3: Determine the regulation of miR-143 and miR-145 by Western diet and 

tumorigenesis. We hypothesize that Western diet and malignant transformation suppress 

transcription, while neoplastic transformation also deranges processing. We will 3a) 

assess effects of ADAM17, diet and neoplastic stage on pri-, pre- and mature levels of 

miR-143, -145 in in vivo models; 3b) dissect EGFR and fatty acid effects on miR-143/-

145 promoter activity using mutant deletions to identify cis regulatory elements; 3c) 

Determine proteins differentially co-associating with biotinylated miR-143 or miR-145 in 

murine processing-competent YAMC and processing-incompetent CT26 colon cancer 

cells to discover deregulated processing factors. Our proposal will clarify the role of 

ADAM17 and test a novel hypothesis that EGFR and these miRNAs form a selfamplifying loop that drives diet-promoted tumorigenesis. 
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Title: Feasibility of Virtual Agent Cervical Cancer Education for 

Hispanic Farmworkers

P.I.: Kristen Jennifer Wells 

Institution: University of South Florida 

Grant No.: CA167418-01A1

Award: $100,000

Latinas experience higher cervical cancer (CC) incidence and mortality when compared 

to the general population in the United States. Many Latinas lack access to health care 

and experience literacy, communication, and knowledge barriers that prevent them from 

obtaining CC screening. Patient navigator (PN) and other similar interventions have been 

implemented to increase CC screening rates; however, few have focused directly on the 

needs of Latinas. Interactive technological interventions, like embodied conversational 

agents (ECA), are currently used in other populations, settings, and for other health 

topics, but no known initiative has used culturally and literacy appropriate technology to 

deliver Spanish-language CC education as part of a PN intervention. This study aims to 

create and conduct a preliminary evaluation of a Spanish-language Virtual Patient 

Educator (VPE) multimedia application to augment a PN intervention for increasing CC 

screening rates among Latinas in a rural agricultural community. Using the Social 

Cognitive Theory, the proposed project will be conducted in 2 phases. In Phase 1, the 

research team will engage community members to develop a low literacy Spanishlanguage interactive multimedia application consisting of an ECA. Using theoretical 

principles and drawing from our formative research, the project team will design the VPE 

through systematic and technical processes. Ongoing feedback (usability testing) from 

members of the intended audience will be carried out to ensure that patients (users) can 

perform intended system tasks efficiently, effectively, and satisfactoril. Once usability 

testing is complete, a series of learner verification interviews will be conducted t assess 

initial suitability of the VPE. Since the VPE will be the first known Spanish-language 

ECA used to augment a PN intervention, it is important to see whether patients accept the 

VPE and whether it is feasible to conduct a study of patient navigation augmented by the 

VPE. In Phase 2, a preliminary evaluation of 2 methods of patient navigation delivery 

(with and without VPE) will be conducted with 60 participants who are not up to date 

with recommended CC screening according to American College of Gynecologists and 

Obstetricians’ guidelines. Cluster randomization will be used to randomize patients to 1 

of 2 PN intervention conditions: (1) PN; or (2) PN plus VPE (PN+VPE) using date of 

clinic as unit of randomization. The preliminary evaluation will examine the feasibility of 

recruitment, randomization, data collection, and acceptability of VPE application. 

Exploratory data will also be collected regarding the potential impact of PN+VPE on 

behavioral capacity and self-efficacy for obtaining CC screening, Pap test adherence, and 

satisfaction with care. The proposed project will advance our research towards the 

development of interactive technology interventions to disseminate health education to 

disparate populations. 

Title: International Pooling Project of Mammographic Density
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P.I.: Valerie McCormack 

Institution: International Agency for Research on Cancer 

Grant No.: CA167771-01

Award: $49,267

Women with a high percentage of fibroglandular tissue in their breast, as opposed to fatty 

tissue, have an increased breast cancer risk (up to 5-fold higher) in the subsequent 10 or 

more years. This attribute, known as mammographic density (MD), varies between 

women and can change within the same woman over time. Having both genetic and 

environmental determinants, between-country differences in MD may account for the 

over 6-fold international variations in breast cancer incidence rates. Only one study has 

investigated this to date, i.e. a US/Hawaii/Japanese comparison (Maskarinec et al. 2007). 

We aim to initiate a more widespread International Pooling Project of Mammographic 

Density to: (i) pool and obtain standardised comparable data on MD from countries 

spanning the breast cancer incidence range; (ii) describe international variations in 

overall and age-specific MD distributions and assess whether they are explained by 

individual-level risk factors for MD; (iii) quantify the extent to which international 

variations in MD correlated with corresponding breast cancer incidence rates and Pike’s 

proposed model of breast tissue ageing; (iv) assess a range of MD metrics 

(absolute/relative/age-specific/cumulative); (v) continue and expand this pooled resource 

into the future. The International Pooling Project of Mammographic Density would be 

the first such initiative for MD, which could later be expanded to include new methods of 

MD measurement, imaging modalities and a broader range of determinants. Being led by 

the International Agency for Research on Cancer, we emphasize an international 

perspective for this marker, especially urgent as breast cancer is now the most common 

cancer in women in almost every country worldwide. If MD does underpin international 

variations in breast cancer incidence, the monitoring of MD-distributions would become 

an important early indicator of changes in breast cancer risk. 

Title: Using Technology To Promote Activity in Women at Elevated 

Breast Cancer Risk

P.I.: Lisa Anne Cadmusbertram 

Institution: University of California at San Diego 

Grant No.: CA168450-01

Award: $67,371

Obesity (i.e., excess energy intake and inadequate physical inactivity) is associated with 

increased risk of breast cancer among postmenopausal women. Effective and practical 

intervention strategies are needed to address the high prevalence of excess weight and 

sedentary lifestyle in middle-aged and older US women. Although web-based 

interventions to promote a healthy lifestyle are common, no studies have tested the use of 

web-integrated physical activity meters for promoting behavior change in this population. 

By leveraging innovative technology-based approaches, researchers and physicians may 

be able to replace intensive physical activity interventions with low-cost alternatives. 

OBJECTIVE: To test the feasibility of using a web-based self-monitoring technology 
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(the FitBit) to promote physical activity among women at elevated risk for breast cancer 

(i.e., overweight/obese, inactive postmenopausal women). SPECIFIC AIMS: This pilot 

study proposes to use a 16-week randomized controlled trial of a novel intervention 

(FitBit activity monitor + training) vs. a pedometer to address the following aims: 

Primary aim: To investigate the effect of the FitBit-based intervention vs. provision of a 

pedometer on objective measures of physical activity and sedentary behavior. Secondary 

aim: To examine the acceptability and usage patterns of the device and website. 

METHODS: Fifty participants will be randomly assigned to receive (a) a FitBit monitor 

and training on use of the website or (b) a pedometer. The FitBit is a tiny physical 

activity tracking device that pairs with a website, wirelessly uploading activity data to 

provide the user with an easy-to-understand visualization of her daily activity patterns. 

Goal-setting features are used alongside simple graphs and charts to enhance selfmonitoring of energy balance. Participants will be given a physical activity goal, trained 

in the use of the self-monitoring website, and asked to wear the FitBit clipped to their 

clothing every day for 16 weeks. The primary outcome will be change in MET-hours/day 

of physical activity, as measured by the ActiGraph GT3X accelerometer prior to 

randomization and at 16 weeks. Although this is a pilot study, we will have 80% power to 

observe an effect size of 0.7 at a significance level of p<0.10. Questionnaires will be used 

to measure intervention acceptability and direct data downloads will provide an objective 

assessment of usage patterns. CANCER RELEVANCE: Promotion of weight 

management and physical activity is an important aspect of breast cancer prevention 

because excess adiposity is associated with increased risk of post-menopausal breast 

cancer. As intervention research evolves, technology offers the potential for cancer 

prevention researchers to move away from costly traditional interventions toward easily 

disseminated interventions that can continue after the study has ended. 

Title: HPV Vaccine Development and Evaluation

P.I.: Allan Hildesheim 

Institution: NCI Intramural Division of Cancer Epidemiology and Genetics 

Research Project

Grant No.: N261200100007

Award: $400,000

ORWH has collaborated with the NCI on the development and evaluation of the 

prophylactic virus-like particle (VLP) human papillomavirus (HPV) vaccine that was 

discovered by investigators at the NCI. In the late 1990s, ORWH supported efforts to 

conduct animal studies and an early phase I human trial in the United States that were 

critical to demonstrating the potential for this vaccine. Subsequently, ORWH supported 

the multiyear, community-based randomized, phase III trial of the HPV vaccine 

conducted by NCI in Costa Rica. This is the only publically funded trial of an HPV 

vaccine. Results from the study in Costa Rica, which is ongoing, have shown that 1) the 

vaccine is highly effective at preventing new infections with HPV types 16 or 18, 2) the 

vaccine confers partial protection against HPV types phylogenetically related to HPV 16 

or 18, 3) the vaccine does not help treat existing infections, 4) fewer than 3 doses of the 

vaccine protects as well as the full 3-dose series for at least 4 years, 5) levels of 
14

antibodies achieved long-term following two doses (0 and 6 months) of the HPV vaccine 

are high and only slightly lower than those observed after three doses of the vaccine, 

likely explaining why fewer than three doses provided a high degree of protection , 6) the 

vaccine protects against HPV infection at the anus, 7) the vaccine protects against HPV 

infection in the oral cavity, 8) vaccine impact declines with increasing age at vaccination, 

9) vaccination induces cross-neutralizing potential in sera of vaccinated individuals, and 

10) modest levels of antibodies generated by natural HPV infection provide partial 

protection against re-infection. Efforts in Costa Rica are ongoing and completion of 10 

years of follow-up of trial participants is expected within the next 4-5 years so that longterm effects of the vaccine (efficacy, safety and immunogenicity) can be fully evaluated. 

During the FY11-FY12 period, ORWH support enabled expansion of the work in Costa 

Rica to include 1) an assessment of vaccine efficacy at sites other than the cervix (anus 

and oral cavity) and 2) investigation of the immunological mechanisms/parameters that 

might explain why this vaccine is effective even when fewer than the recommended three 

doses are administered and against HPV types not included in the vaccine formulation. 

Title: Research and Studies on the Effects of Inflammation in Gall 

Bladder Cancer

P.I.: Ann Hsing and Jill Koshiol

Institution: NCI Intramural Research Project

Grant No.: N26100003

Award: $200,000

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

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

women) are observed in Chile. Investigators in the Infections and Immuno-epidemiology 

Branch (IIB) are evaluating the feasibility of conducting a case-control study of 

gallbladder cancer in Chile to better understand the causes of this disease. As currently 

envisioned, the initial pilot effort will define whether such a study would be successful at 

identifying and enrolling cancer cases, controls with gallstones (an important precursor 

for this cancer) and controls form the general population. We are working with well 

established investigators in the region with a proven track record of conducting 

epidemiological investigations to maximize the likelihood of success. A case-control 

study of gallbladder cancer in Chile would permit us to elucidate the role of obesity (and 

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

genetic susceptibility factors in the etiology of this tumor. This study could have 

important public health implications, since cholecystectomies are currently being 

recommended for women for the prophylaxis of gallbladder cancer in this high risk area. 

A better understanding of the causes of this disease could lead to the development of 

better and less aggressive preventative measures against this disease.

Title: California Health Interview Survey

P.I.: David Grant

Institution: University of California, Los Angeles
15

Grant No.: N261200544000C

Award: $200,000

California Health Interview Survey (The California Health Interview Survey (CHIS) is 

the largest and most comprehensive state health survey in the U.S. It provides valid local 

and state estimates for California. Conducted by telephone in English, Spanish, Chinese, 

Korean and Vietnamese, CHIS interviews a representative sample of over 40,000 adults 

in California households. Since its inception in 2001, NCI has supported cancer control 

items on CHIS, and ORWH provided funding for FY12. CHIS data are publicly released. 

CHIS data are widely accessible to policy makers, stakeholders and researchers via the 

AskCHIS calculator, public use data, and micro-data files (http://www.chis.ucla.edu/). 

Title: National Longitudinal Mortality Study

P.I.: Paul Sorley (NHLBI)

Institution: NHLBI, NIA, NCI, and Centers for Disease Control and 

Prevention/National Center for Health Statistics, in collaboration 

with the U.S. Census Bureau

Grant No.: 0081-1998-005

Award: $200,000

The National Longitudinal Mortality Study (NLMS) database is a population-based 

resource for studies of relationships between lifestyle factors, socioeconomic status (SES) 

and mortality. Advantages of the NLMS database compared to other large prospective 

studies include annual enrollment of nationally representative household samples with 

self-reported socioeconomic status. The study is designed to yield a sample reflecting the 

national population with respect to race, ethnicity and SES with precise estimates through 

weighting to adjust for under-sampling. ORWH contributed FY 2012 funding to update 

NLMS matches to the National Death Index through 2010. The updated match is an 

opportunity to advance understanding of factors affecting women’s health and mortality 

experience in the United States. The NLMS Steering Committee includes representatives 

of three NIH Institutes: the National Heart Lung and Blood Institute, National Institute on 

Aging, and National Cancer Institute and CDC’s National Center for Health Statistics and 

the Census Bureau. The Steering Committee facilitates research proposals from 

intramural and extramural investigators. More than 130 collaborators have used the 

dataset to publish over 70 journal articles in JAMA, British Medical Journal, Lancet, 

American Journal of Epidemiology, Archives of Internal Medicine, Cancer, Stroke, and 

the American Journal of Public Health. Articles have also been published in 

Demography, Ethnicity and Disease, Gender Medicine, Journal of Aging and Health, 

Journal of Health and Social Behavior, Journal of Rural Health, Psychological Medicine, 

and Social Science and Medicine. 

Title: DCEG/EBP Intramural—Follow-up of DES Cohorts

P.I.: Jessica Mills 

Institution: Boston University
16

Grant No.: 261201000128C*3

Award: $18,750

Since 1992, DCEG and other NCI investigators, along with collaborators from five field 

study centers, have been actively following diethylstilbestrol (DES) exposed and 

unexposed mothers, daughters and sons, and granddaughters for adverse health effects 

resulting from this exposure. As DES-exposed offspring are currently reaching the age 

when cancer rates begin to rise, it is important to continue to monitor long-term risk of 

cancer and other adverse health outcomes in this unique population. The study also 

provides a model for assessing a number of hypotheses that address concerns about 

prenatal hormonal influences on disease risk, both an intriguing area of science and an 

increasingly controversial environmental issue that affects a substantial proportion of the 

population.

To date the study has identified excess female breast cancer after age 40 that shows a 

dose-response effect, as well as increased risk for high-grade lesions of the cervix and 

vagina. Concern over other hormone-related cancers remains; though to date analyses 

have been limited due to small numbers of cases. In the sons, investigators observed an 

excess risk for urogenital anomalies and infertility, and a likely excess of testicular 

cancer. To examine the effects in the third generation (the daughters of the prenatally 

exposed daughters), investigators assembled a small cohort in 2000. Given their average 

age, there have been few relevant disease outcomes. However, investigators noted an 

elevated risk for infertility—though not statistically significant, this outcome was also 

seen in DES-daughters. In addition, there were three cases of ovarian cancer in the 

granddaughters, even though substantially less than one had been expected. While both of 

these observations remain difficult to interpret, they have added some urgency to expand 

the cohort and continue to follow-up.

Since 1992, DCEG and other NCI investigators, along with collaborators from five field 

study centers, have been actively following diethylstilbestrol (DES) exposed and 

unexposed mothers, daughters and sons, and granddaughters for adverse health effects 

resulting from this exposure. As DES-exposed offspring are currently reaching the age 

when cancer rates begin to rise, it is important to continue to monitor long-term risk of 

cancer and other adverse health outcomes in this unique population. The study also 

provides a model for assessing a number of hypotheses that address concerns about 

prenatal hormonal influences on disease risk, both an intriguing area of science and an 

increasingly controversial environmental issue that affects a substantial proportion of the 

population.

To date the study has identified excess female breast cancer after age 40 that shows a 

dose-response effect, as well as increased risk for high-grade lesions of the cervix and 

vagina. Concern over other hormone-related cancers remains; though to date analyses 

have been limited due to small numbers of cases. In the sons, investigators observed an 

excess risk for urogenital anomalies and infertility, and a likely excess of testicular 

cancer. To examine the effects in the third generation (the daughters of the prenatally 

exposed daughters), investigators assembled a small cohort in 2000. Given their average 
17

age, there have been few relevant disease outcomes. However, investigators noted an 

elevated risk for infertility—though not statistically significant, this outcome was also 

seen in DES-daughters. In addition, there were three cases of ovarian cancer in the 

granddaughters, even though substantially less than one had been expected. While both of 

these observations remain difficult to interpret, they have added some urgency to expand 

the cohort and continue to follow-up.

Title: Pharmacotheraphy Evaluation Tools for Improving Breast 

Cancer Outcomes in Rural Appalachia

P.I.: Rajesh Balkrishnan 

Institution: University of Michigan at Ann Arbor 

Grant No.: CA168479-01

Award: $200,000

Access to effective breast cancer care is a critical factor in Appalachia contributing to 

health disparities among this population. Poor adherence to adjuvant cancer treatment has 

been reported to increase risk of death and associated with increased medical costs in 

breast cancer. Patient medication use behaviors are critical to the cancer heath disparities 

in Appalachia, and research on essential medication use and quality in rural areas is scant. 

Data suggests that designing an effective intervention targeting determinants of access to 

cancer care in Appalachia will provide patients an opportunity to receive appropriate 

medical treatment to alleviate disparity in cancer morbidity and mortality. The major 

impact of this study will be the production of a concrete intervention design aimed at 

reducing cancer health disparities in Appalachia by targeting modifiable contributors 

such as accessibility of medical care, quality and quantity of pharmacological treatment 

delivery, and adherence behaviors and their determinants. The purpose of this application 

includes an innovative approach to model accessibility to cancer care resource influences 

guiding appropriate treatment delivery and medication use behaviors (persistence and 

adherence to prescribed treatment), and how such factors impact cancer survival. Our 

central hypothesis is that patients who are able to access adequate medical care are more 

likely to receive standard treatments and persistently follow recommendations which lead

to better therapeutic outcomes (such as survival). The strategies proposed will address the 

following specific aims: 1) Assess the complexity of the relationship between access to 

cancer care resources and patient prescribed guideline appropriate for adjuvant cancer 

treatments, 2) Delineate the manner in which specific social, system-specific, and 

individual determinants of access to cancer care affect patient medication use behaviors 

of persistence and adherence, and 3) Model cancer survival as a function of patient and 

system specific dimensions of access to cancer care, prescribing guideline appropriate 

adjuvant treatment and medication use behaviors. This study will use a unique NCIfunded linked dataset of 7,566 patients with breast cancer assembled from cancer 

registries, Medicare and Medicaid Services (CMS) Medicare claims data, US Social 

Security Administration’s Death Master File (DMF), American Medical Association 

(AMA) Master file for information on physician and practitioners, American Hospital 

Dictionary (AHD) for healthcare facility characteristics. We hypothesize that there are 

modifiable individual and health-system related factors that impact the patient’s receipt 
18

of optimal pharmacological treatment. The rationale for the proposed study is that, once 

medication access and utilization factors to which disparity in cancer survival can be 

attributed, are identified and accurately modeled, effective interventions targeting 

influential factors for breast cancer survival can be developed and tested in the same 

population and adapted to other populations burdened with similar inequalities, resulting 

in reducing health disparity in Appalachia and other regions.

Title: Bedside to Bench—Molecular Epidemiology of Postpartum 

Involution of the Breast: Demonstration of Tools for 

Understanding Influences of Pregnancy on Breast Cancer Risk

P.I.: Mark Sherman

Institution: City of Hope

Award: $90,000

Experimental and observational data implicate postpartum breast remodeling in the 

pathogenesis of early onset aggressive breast cancers (reviewed, J Mammary Gland Biol 

Neopl June 2009), a disease that disproportionately affects African Americans. Recent 

studies of animal models suggest that an inflammatory wound response related to 

remodeling promotes progression of in-situ to invasive cancer, and that this effect can be 

blocked by anti-inflammatory drugs (Nat Med 2011). In addition, our collaborator, Dr. 

Kathleen Arcaro, has developed immunomagnetic methods to isolate epithelial cells shed 

in milk and assess DNA methylation of tumor suppressor genes involved in breast cancer. 

Using this technique, she has preliminarily demonstrated detection of pregnancy 

associated breast cancers (AACR 2011). 

This proposal would refine tools for studying women through the early postpartum period 

to understand the effects of pregnancy and lactation on the breast. These tools will 

include novel methods of sampling breast epithelial cells shed in milk and MRI imaging. 

We will preliminarily explore hypotheses related to specific candidate mechanisms and 

biomarkers that have been implicated in postpartum re-modeling or may predict breast 

cancer risk by comparing data from lower risk uniparous women, defined as younger or 

White, as compared to higher risk women, defined as older or African American. Bench 

aims will include: improved milk collection, fractionation and optimization of milk 

assays, including DNA methylation analysis and measurement of hormonal and 

inflammatory markers. Bedside aims include: collection of milk at two time points to 

assess molecular markers for comparison over time within subjects, and between 

subjects, stratified by race and age, and to assess a subset of the same subjects during this 

period by MRI at the NIH Clinical Center.

To pursue our aims, we will leverage a unique collaboration between CCR, extramural 

collaborators and NCI/DCEG investigators with broad interests in breast biology and 

cancer. The proposed collaboration will include: 1) Jane Balkam, R.N., Ph.D., an expert 

lactation consultant with the NIH Work Life program; 2) David Bluemke, M.D., Ph.D., 

Chief of Radiology at NIH who will develop MRI studies; 3) Kathleen Arcaro, Ph.D., a 

laboratory scientist at the University of Massachusetts who has developed methods to 
19

isolate epithelial cells from milk for analysis of DNA methylation in tumor suppressor 

genes and will work with Dr. Sherman to optimize fractionation and assays and 5) DCEG 

investigators with interests in breast cancer epidemiology, including early life events, 

genetics, breast density, hormones and molecular pathology. Dr. Hewitt will work with 

Dr. Sherman to prepare cells for pathologic analysis, Dr. Faupel-Badger will evaluate 

hormone assay data, Dr. Gierach will interpret MRI data and provide epidemiological 

expertise and Dr. Meeker will perform telomere assays. Dr. Sherman will serve as PI and 

will lead the project, as well as providing expertise related to breast biology, pathology 

and molecular epidemiology. Dr. Arcaro, as extramural PI, will provide unique expertise 

on milk processing and performing DNA methylation assays on cells shed in milk.

National Eye Institute 

Title: Surveillance and Treatment of Community Newcomers and 

Travelers for Trachoma Control

P.I.: Sheila K. West 

Institution: Johns Hopkins University 

Grant No.: EY022584-01S1

Award: $40,000

Infection with C. trachomatis has decreased substantially in trachoma endemic areas 

following repeated annual mass drug administration with azithromycin, although not as 

rapidly as anticipated. We propose to conduct a clinical trial to determine the added 

benefit for communities, which are now at low levels of infection, of a program to 

identify and treat new families who came after mass treatment, and travelers who return 

to the community, as they could be the source of re-emergent infection. The proportion of 

communities who are able to stop mass treatment will be compared in the group of 

communities randomized to mass treatment plus the newcomer treatment program 

compared to the communities randomized to mass treatment alone. 

Title: Broad Spectrum Molecular Therapy for Blinding Retina 

Disorders

P.I.: Jean Bennett 

Institution: University of Pennsylvania 

Grant No.: EY023177-02

Award: $150,000

This proposal evaluates the translational potential of optogenetic therapy, an approach 

whereby visual function is achieved through the use of a molecular prosthesis that 

transmits its signals to downstream visual circuits. Studies in vitro and in vivo in animal 

models by our collaborators (and others) have demonstrated that light-activated chloride 

pumps or channels can be introduced into specific retinal cell types in diseased or 

atrophic retinas. There, these molecular prostheses can permit visual responses where 

before, there were none. The present program aims to address the knowledge gaps and 
20

technical limitations relevant to development of optogenetic therapy in two different 

paradigms: 1) Physiologically optimized forms of Halorhodopsin (NpHR) will be used to 

activate function of failing cone photoreceptors after the rod photoreceptors have 

degenerated; 2) Optimized Channelrhodopsins (ChRd) will be used to confer light 

responsiveness to second order retinal neurons in degenerated retinas. We will design and 

develop the appropriate vectors, delivery strategies and outcome measures for each 

paradigm, will carry out the prerequisite preclinical safety and efficacy studies, and will 

bring one of the studies (NpHR) to clinical trial. In the process, novel strategies of 

altering the transduction characteristics of adeno-associated virus (AAV) will be 

developed, new surgical approaches which could be applied to human eyes will be 

devised, and sensitive, noninvasive, clinically relevant outcome measures will be defined. 

Simultaneous with development of the technology, we will evaluate the bioethics of gene 

therapy-mediated delivery of molecular prostheses in humans. This comprehensive 

program benefits greatly from the wisdom and experience of many talented collaborators 

and advisors and takes advantage of the infrastructure that the PI has already developed 

for ocular gene therapy translational research. 

National Heart, Lung, and Blood Institute

Title: Endogenous Cardiac Repair in Humans

P.I.: Kenneth Ber Margulies 

Institution: University of Pennsylvania 

Grant No.: HL089847-04S1

Award: $72,000

Until recently, the heart has been viewed as a terminally differentiated organ with no 

capacity for new cardiac myocyte (CM) formation. This view appears to be incorrect, in 

that we and others have been able to isolate cardiac-derived progenitor cells (CDPCs) 

from human myocardium. Extending these results, our recent studies indicate that cells 

expressing the stem cell surface marker c-kit can be isolated from human hearts 

immediately after explantation and subsequently induced to differentiate into CM via 

short-term co-culture with neonatal rat ventricular myocytes (RVMs). Though we 

typically find more c-kit+ cells usually in failing vs. nonfailing hearts, the need to replace 

these failing hearts via transplantation highlights the inadequacy of native cardiac repair 

mechanisms. Based on these findings, our broad working hypothesis is that increased ckit+ CDPCs in failing human hearts include both lineage-negative c-kit+ and ckit+/CD45(dim-moderate) cells that are each capable of new myocyte formation in vitro. 

In this context, the objective of this proposal is to quantify and characterize these distinct 

subpopulations of stem/progenitor cells within human hearts with an emphasis on 

elucidating their functional capacity for replication and CM differentiation. Our first aim 

is to identify what types of stem/progenitor cells are present in normal and failing human 

hearts. We will define distinct stem/progenitor subpopulations based on immunotyping of 

disaggregated myocardial cells with fluorescence microscopy and flow cytometry and 

perform complementary studies in tissue sections from the same hearts to define their 

distribution. Our second aim is to characterize replicative capacity of the selected CDPC 
21

subpopulations based on a combination of static assays (telomere length, telomerase 

activity and and p16INK4a expression) and functional assessment of proliferation rates. 

Our third aim is to characterize the cardiac myogenic potential of selected CDPC 

subpopulations derived from human hearts. These studies will define the rates and 

frequency of CM differentiation for sorted subpopulations under stardardized co-culture 

conditions, define whether cell contact is required for induction of CM differentiation by 

neonatal rat myocytes and identify secreted factors (chemokines or growth factors) that 

promote or augment rates of in vitro CM diffentiation in selected CDPC subpopulations. 

The clinical/therapeutic significance of this proposal is based on the premise that insights 

into the proliferative and cardiomyogenic potential of endogenous cardiac 

stem/progenitor cell subpopulations will promote progress towards therapeutic cardiac 

regeneration with or without cell therapy per se. 

Title: Avoiding Toxicity Associated with MTP Ablation

P.I.: M. Mahmood Hussain 

Institution: SUNY Downstate Medical Center 

Grant No.: HL095924-03S1

Award: $20,000

High plasma lipids and lipoproteins are risk factors for various cardiovascular and 

metabolic disorders. An approach to lower plasma lipids is to inhibit apoB-lipoprotein 

biosynthesis, a process critically dependent on an endoplasmic reticulum (ER) resident 

chaperone, microsomal triglyceride transfer protein (MTP). MTP inhibitors decrease 

apoB-lipoprotein secretion and lower plasma cholesterol. However, they increase plasma 

aminotransferases, such as ALT and AST, indicating liver injury. We hypothesize that 

increases in plasma hepatic enzymes associated with MTP inhibition are due to increases 

in microsomal free cholesterol, induction of ER stress and cell death. We further 

hypothesize that reducing cellular free cholesterol along with MTP inhibition might 

reduce hyperlipidemias and avoiding toxicities associated with MTP antagonists. In the 

first aim, Alb-Cre-MTPfl/fl or MTPfl/fl mice will be fed T-0901317, a LXR agonist to 

induce free cholesterol efflux; lovastatin, a HMG Co-A reductase antagonist to inhibit 

cellular cholesterol biosynthesis; or WY14643, a PPAR945; agonist to enhance 946;-

oxidation of fatty acids, for 3 or 24 weeks. In another group, 937;-3 fatty acids, 

PPAR945;/948; agonists, will be injected intraperitoneally to reduce hepatic triglyceride 

and free cholesterol. In addition, Alb-Cre-MTPfl/fl mice will be fed a western diet and 

then treated with T-0901317, lovastatin, WY14643, or &-3 fatty acids. Experiments will 

then be performed in C57Bl/6J mice fed a western diet and fed daily with MTP 

inhibitors. Additionally, they will be fed olive oil alone or with other compounds 

described above to determine if toxicities associated with MTP inhibitors can be avoided 

by these treatments. Outcome measurements will involve changes in apoB-lipoproteins 

and hepatic enzymes in the plasma; hepatic triglycerides, esterified cholesterol, and free 

cholesterol; quantification of candidate mRNAs and proteins involved in cholesterol and 

triglyceride biosynthesis, ER stress, as well as AST/ALT isoforms. These studies will 

show that toxicities associated with MTP inhibition can be avoided by reducing hepatic 

free cholesterol. The second aim is to test the hypothesis that release of hepatic enzymes 
22

in the plasma is due to the induction of the ER stress and apoptosis. We will first 

demonstrate that MTP inhibition increases microsomal free cholesterol. Second, we will 

identify the ER stress pathways activated by MTP ablation/inhibition. Third, we will 

establish that MTP inhibition induces apoptosis. Fourth, a link between the ER stress and 

induction of apoptosis will be established. Fifth, importance of the ER stress pathways 

will be substantiated using ATF6-/-, CHOP-/- and Alb-Cre-Ire11fl/fl mice fed MTP 

inhibitors. Sixth, we will determine if induction of ER stress by tunicamycin increases 

plasma AST/ALT levels. At the completion of these studies, we will find out molecular 

mechanisms responsible for unwanted side effects associated with MTP therapy and 

suggest solutions to avoid these toxicities. These studies may lead to new therapeutic 

modalities for the treatment of various hyperlipidemias and have immediate potential for 

translational use.

Title: Saturated Fat and Protein Effects on Atherogenic Dyslipidemia

P.I.: Ronald M. Krauss 

Institution: Children’s Hospital & Research Center Oakland 

Grant No.: HL106003-02S1

Award: $200,000

The overall objective of this project is to test the hypothesis that the effects of saturated 

fat (SF) on lipoprotein markers of cardiovascular disease (CVD) risk are influenced by 

food sources of dietary protein. There is growing epidemiological evidence that 

consumption of red meat is associated with greater incidence of CVD than either white 

meat or non-meat foods. Pathophysiological support for the validity of this association is 

provided by preliminary evidence from our group that a high beef diet has a more 

deleterious effect on lipoprotein measures of CVD risk than we have observed for mixed 

protein diets. Specifically, we have found that a high protein, high SF diet with a 

moderate red meat content selectively induces increases in intermediate density 

lipoproteins (IDL) and larger LDL particles that have been found to be much more 

weakly associated with CVD risk than smaller LDL. In contrast, a more recent study 

from our group has found that, with a similar intake of SF, high beef consumption results 

in a preferential increase in levels of small and medium sized LDL particles, both of 

which are strongly related to incident CVD. To date however, no studies have directly 

compared the lipoprotein effects of red meats with other food sources of protein in the 

context of both high and low saturated fat intake. We specifically hypothesize that 

increases in plasma levels of LDL cholesterol (C), and apolipoprotein (apo) B, induced 

by SF are greater when the major food source of protein is red meat rather than either 

white meat (poultry) or non-meat foods, and that this is due to increased levels of small 

and medium sized LDL particles. We therefore propose a clinical trial in which 180 

healthy men and women will be randomized to high SF (15%) or low SF (7%) diet

groups, and within each group, consume diets with equivalent amounts of protein derived 

from red meat, white meat, and non-meat sources for 4 wk each in random order. Our 

Specific Aims will test whether: (1) with high SF, the red meat diet, compared to the 

other food sources of protein, will result in higher levels of LDL-C, apoB, small and 

medium sized LDL particles, and total/HDL-C; (2) with low SF, dietary protein source 
23

will not be related to any of these measurements; (3) with both the white meat and nonmeat diets, increased LDL-C with high vs. low SF will be due primarily to increases in 

IDL and/or large LDL, whereas with red meat the additional increase in small and 

medium LDL will result in greater increases in apoB. In addition to these aims we will 

test for possible metabolic determinants of dietary effects on apoB-containing lipoprotein 

subclasses, including post-heparin plasma hepatic lipase activity, which is critical for 

production of smaller LDL, and LDL receptor activity as assessed in peripheral blood 

mononuclear cells, a system demonstrated to reflect physiologically relevant LDL 

receptor regulation. Finally, we will examine potential dietary influences on other 

metabolic biomarkers of CVD risk, including HDL subclasses and apoproteins, insulin 

sensitivity as assessed by HOMA-IR, measures of inflammation including CRP and 

multiple cytokines, and endothelial function using a non-invasive fingertip method. 

Title: Molecular Mechanism of Platelet Dense Granule Biogenesis

P.I.: Santiago Mauro Di Pietro 

Institution: Colorado State University 

Grant No.: HL106186-01A1S1

Award: $20,000

Platelets play pivotal roles in both hemostasis and thrombosis. Platelet activation triggers 

secretion and the release of content from dense granules, a-granules, and lysosomes that 

in turn leads to the recruitment and aggregation of additional platelets and white cells. 

While impaired platelet function has been associated with disorders that manifest with 

moderate to severe mucocutaneous bleeding, excessive platelet aggregation is a major 

cause of morbidity and mortality due to its effect in myocardial infarction and stroke. In 

spite of the relevance of platelet dense granules for human health, little is known about 

their biogenesis. Therefore, our goal is to understand the molecular mechanism 

responsible for the biogenesis of platelet dense granules. Dense granules belong to a 

group of lysosome-related organelles (LROs). Formation of LROs involves two parallel 

protein transport pathways defined by Adaptor Protein-3 (AP-3) and Biogenesis of 

Lysosome-related Organelles Complex-2 (BLOC-2). AP-3 is an adaptor that selects 

proteins with specific targeting signals in early endosomes and packages them into 

vesicles for transport to LROs. BLOC-2 also localizes to early endosomes but its function 

is unknown. We have recently obtained preliminary evidence suggesting that BLOC-2 

has adaptor-like properties but with the ability to bind new targeting signals in dense 

granule proteins, different from the signals recognized by AP-3. Moreover, we obtained 

substantial preliminary results indicating that five proteins are fundamental components 

and new players in the pathways to dense granules: two “molecular switches”, two novel 

proteins containing vesicle scission domains, and a molecular motor. These findings have 

opened new avenues to study the biogenesis of platelet dense granules. We propose to: 

(1) establish new in vitro and in vivo systems to study the biology of dense granules, (2) 

test the hypothesis that new dense granule targeting signals exist in dense granule 

proteins and that BLOC-2 is an adaptor that recognizes these signals and packages the 

corresponding proteins into vesicles destined for dense granules; (3) test the hypothesis 

that tissue specific “molecular switch” proteins recruit AP-3, BLOC-2, and other 
24

ubiquitous components to endosomal membranes to specifically direct transport to dense 

granules; (4) test the hypothesis that new vesicle scission and molecular motor proteins 

mediate the formation and transport of vesicles loaded with dense granule membrane 

proteins to dense granules; and (5) test the possibility that numerous patients that present 

in the clinic with platelet type bleeding disease of unknown etiology may have 

deficiencies in these new molecular switches, scission, and molecular motor proteins 

involved in dense granule biogenesis. 

Title: Uterine-Specific Genetic Modification and 

Lymphangioleiomyomatosis

P.I.: Jose M. Teixeira 

Institution: Massachusetts General Hospital 

Grant No.: HL109935-02

Award: $50,000

Lymphangioleiomyomatosis (LAM) is a rare disease primarily found in females and is 

characterized by a diffuse interstitial infiltrate of atypical smooth muscle cell lesions in 

the lung parenchyma resulting in airway restriction. The etiology of the disease is 

unknown but is thought to involve hormonal regulation because it usually presents 

between menarche and menopause. Additionally, LAM is often found in patients with 

mutations in tuberous sclerosis complex (TSC), suggesting that inactivation of TSC can 

contribute to its development. We are studying uterine development and associated 

pathologies by conditionally deleting and/or activating candidate genes in pathways 

critical for normal differentiation and function. We have created mice with uterinespecific leiomyomas (fibroids) by either constitutively activating ¿-catenin or by 

expressing a truncated allele of adenomatous polyposis coli (APC) and we have shown 

preliminary evidence that the leiomyomas develop as a result of vascular hemorrhaging 

and subsequent hypertrophic scarring. The Mullerian duct-derived internal female 

reproductive tract organs (uterus, oviduct, cervix, and cranial portion of the vagina) are 

the only structures from the bipotential mammalian embryo not found in males, 

suggesting that the hormonally responsive mesenchymal stromal cells of the uterus might 

be the source of the cells for pulmonary fibrosis and account for the female-specificity of 

LAM. We hypothesized that pulmonary LAM might be caused by uterine vascular 

pathologies that allow intravasation of uterine stromal cells that can subsequently lodge 

and proliferate in the lungs. Histological analysis of the lungs from our mouse models 

with uterine hemorrhaging and leiomyomas showed fibrotic lung plaques similar to that 

observed in human LAM that were also HMB45-, aSMA- and desmin-positive, markers 

for human LAM. We propose to investigate this hypothesis further with the following 

Specific Aims: (1) confirm that cells in the lung lesions are derived from the uterus, (2) 

determine whether uterine mesenchymal cells can be detected in peripheral blood, (3) test 

the hormone responsiveness of the smooth muscle cells in the lung lesions, and (4) assess 

the marker profile of lung lesions for comparison with human LAM. The results from 

these studies will lay the foundation for continued investigation of the triggers and 

signaling pathways involved in the development of the LAM lesions as well as provide 

an in vivo model system for preclinical studies of therapeutics targeting those pathways. 
25

Title: Premenstrual Syndrome and Risk of Subsequent Hypertension

P.I.: Elizabeth R. Bertone-Johnson 

Institution: University of Massachusetts Amherst 

Grant No.: HL115357-01

Award: $195,117

Hypertension is one of the strongest predictors of cardiovascular disease (CVD) in 

women. Despite extensive knowledge of the etiology of hypertension and the availability 

of effective treatments, prevalence remains high. There is a substantial need for novel 

strategies to identify premenopausal women at high risk for hypertension who would 

benefit from early intervention to reduce their long term risk of CVD. Up to 20% of 

premenopausal women meet clinical criteria for premenstrual syndrome (PMS), a 

disorder characterized by moderate to severe luteal phase symptoms that substantially 

interfere with normal life activities and interpersonal relationships. The pathophysiology 

of PMS is complex, and factors including dysfunction of the renin-angiotensinaldosterone system and vitamin D insufficiency likely contribute. Importantly, these 

factors have also been implicated in the etiology of hypertension. Thus, moderate to 

severe PMS may be predictive of increased risk of hypertension later in life, and may 

serve as an early sentinel of CVD risk. The proposed project will extend work completed 

during the Principal Investigator’s current career development award (K01MH07624) to 

explore the relation of PMS with hypertension and blood pressure in two populations of 

women. First, we will determine prospectively if PMS occurring in the middle 

reproductive years is associated with subsequent risk of hypertension and changes in 

blood pressure over time. We have developed a prospective study of PMS nested within 

the Nurses’ Health Study II (NHS2) cohort; to our knowledge, this is the only prospective 

epidemiologic study of women with PMS in existence. The NHS2 PMS Sub-Study 

includes 1257 women meeting established criteria for moderate to severe PMS and a 

comparison group of 2463 women without PMS. As of 2013, participants will have been 

followed for 24 years for incident hypertension and changes in blood pressure, and 

women with PMS will have been observed for up to 20 years following their PMS 

diagnosis. Second, we will determine if common PMS treatments and dietary and 

behavioral factors modify the association of PMS and blood pressure, and thus may 

provide opportunities for women experiencing PMS to reduce their risk of hypertension 

and CVD. Finally, using data from a second study of young adult women (n=375), we 

will determine if differences in blood pressure are already evident in women experiencing 

PMS in their late teens and early 20’s. Data from both studies have already been 

collected, thus providing a cost-effective way to address these novel and important 

questions. IMPACT: This life course study will be the first to evaluate whether moderate 

to severe PMS may serve as an early sentinel of long-term health outcomes. It may help 

identify a population of women at high risk for hypertension who would benefit from 

increased screening and early intervention. Furthermore, it may lead to clinical trials of 

novels strategies for treating PMS, no only to reduce morbidity and improve quality of 

life in women with the disorder, but also to reduce their long-term risk of cardiovascular 

disease. 
26

Title: A Formative Examination of the Health and Safety of Female 

Firefighters

P.I.: Sara Anne Jahnke 

Institution: National Development and Research Institutes, Inc.

Grant No.: HL119024-01A1

Award: $199,800

Firefighters/EMS personnel are vital for public health safety, representing over two 

million individuals nationally. Because firefighters are required to respond to almost 

every domestic emergency, there is wide agreement that their health and readiness is of 

particular importance. Furthermore, a broad range of occupational exposures exist that 

negatively impact the health of firefighters. While the field of firefighter health has 

enjoyed growth over the past decade, the health of female firefighters remains largely 

unexamined. Similar occupational groups, such as the military, have developed focused 

programs to understand the unique work-related challenges to women’s health; however, 

research in the fire service has remained relatively silent on the topic. This dearth of 

informatio likely contributes to the remarkably low rates of females recruited and 

retained by the fire service. While challenges such as harassment in the workplace have 

been identified as concerns for female firefighters, health concerns beyond emotional 

stress have received limited attention. Anecdotal evidence suggests that issues such as 

reproductive health, ill-fitting gear, and on-the-job injuries attributable to standard 

operating procedures and guidelines that do not accommodate differences in female 

characteristics are barriers to women serving as firefighters. The military, a similar 

population with regard to work task, environment, and a tradition of being primarily 

male, has been successful in making female health a priority through the development of 

a focused program of gender specific research. Despite significant cultural barriers, the 

armed forces have been successful in recruitment and retention of female personnel at a 

rate that far exceeds the US fire service. In this proposed project, we will use a multimethods research design to examine health and safety issues among female firefighters. 

In addition, this study will identify factors which serve as barriers to recruitment and 

retention of women in the fire service. Unique strengths of this R21 developmental 

application include strong support from the largest national fire service organization 

focusing on women and an investigative team with a documented history of successful 

research on the health of firefighters. Research for this formative research will be 

conducted in three phases including: 1) focus groups with a national sample of female 

firefighters, and key informant interviews with male and female fire service opinion 

leaders; 2) key informant interviews with female firefighters who have chosen early 

retirement to determine barriers to retention among this population and 3) an 

epidemiological survey of a sample of female firefighters to determine current health 

status and health concerns across a number of domains. This innovative study is a critical 

step in addressing gender inequity of the US Fire Service and identifying areas of 

intervention and prevention for this understudied occupational group. 
27

National Institute on Aging

Title: SWAN: Study of Women’s Health Across the Nation

P.I.: Joel S. Finkelstein 

Institution: Massachusetts General Hospital 

Grant No.: AG012531-19

Award: $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. 

We 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 IV project 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 
28

40-55 years who were screened during 1995-1997, 3302 women aged 42-52 years were 

enrolled in SWAN’s longitudinal cohort (approximately 450 at each of 7 clinical centers). 

They completed their baseline clinic visit during 1996-1997. Of the 3302 women 

enrolled, 1550 were Caucasian, 935 African American, 286 Hispanic, 250 Chinese, and 

281 Japanese. A subset of 880 menstruating women was enrolled in the Daily Hormone 

Study (DHS) started in 1997, which is designed to examine cyclical daily hormone and 

symptom patterns during the menopausal transition. 

Title: Study of Women’s Health Across the Nation—Coordinating 

Center

P.I.: Kim Sutton Tyrrell 

Institution: University of Pittsburgh at Pittsburgh 

Grant No.: AG012553-18

Award: $125,000

The Study of Women’s Health Across the Nation (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 we 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 our 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. RELEVANCE: 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 
29

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. 

Title: Effects of Aging on Visual Memory: Neuroimaging Studies

P.I.: Roberto Cabeza

Institution: Duke University

Grant No.: AG019731-10

Award: $200,000

Aging is associated with substantial deterioration of the visual system and associated 

sensory-perceptual processes. This decline in visual processing is a strong predictor of 

cognitive decline in healthy aging and of Alzheimer’s disease. Yet, the effects of aging 

on visual processing and cognitive functions, such as memory, have typically been 

investigated independently of each other. Filling this void, the proposed neuroimaging 

studies focus on the interactions between age effects on visual and memory processes, 

and the brain regions mediating these processes. This significant goal is combined with 

an innovative multi-measure methodological approach which assesses age effects (1) on 

visual and memory performance using behavioral tests; (2) on brain activity in occipitotemporal, medial temporal, prefrontal regions using functional MRI (fMRI); (3) on the 

interactions among these regions using functional connectivity (fCON); and (4) on the 

integrity of the white-matter fiber tracts connecting these regions using diffusion tensor 

imaging (DTI). Most importantly, these different measures are directly linked to each 

other. The multi-measure approach is applied to three specific aims. Specific Aim 1 is to 

investigate the role of peripheral and top-down modulation deficits in visual memory 

impairments in older adults. Older adults show reduced activity and selectivity 

(dedifferentiation) in occipito-temporal cortex, which may reflect peripheral or top-down 

modulation deficits. Study 1 compares the effects of divided attention, which interferes 

with top-down modulation, and stimulus degradation, which mimics age-related 

peripheral visual deficits. Study 2 employs overlapping face-house stimuli to examine 

selective attention deficits. Specific Aim 2 is to investigate the role of perceptual and 

conceptual processing deficits in visual memory impairments in older adults. Conceptual 

processing enhances memory for meaningful visual stimuli such as objects but, when 

combined with perceptual processing deficits, can lead to false memories. Study 3 

investigates age effects on conceptual vs. perceptual processing during the encoding of 

meaningful objects. Study 4 examines age effects on encoding leading to true vs. false 

memory for objects. Specific Aim 3 is to investigate the role of retrieval reactivation 

deficits in visual memory impairments in older adults. Visual memory depends not only 

on visual cortex activations during learning but also on visual cortex reactivations when 

visual events are remembered. Study 5 investigates age effects on the reactivation of 

memories for familiar faces and objects. Linking with Specific Aim 2, Study 6 

investigates the reactivation of perceptual and conceptual representations. The proposed 

studies will be the first to systematically investigate the neural mechanisms of age-related 

visual memory decline. Their results will have direct implications for the development of 

treatments for memory decline in healthy aging. Moreover, given that visual memory 
30

decline predicts Alzheimer’s disease a decade before diagnosis, the results will also have 

implications for the early detection and treatment of this disease. 

Title: National Social Life, Health, and Aging Project

P.I.: Linda J. Waite 

Institution: National Opinion Research Center 

Grant No.: AG030481-05

Award: $200,000

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. We 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. We propose to revisit respondents four 

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

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

social context. In each case, we 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. We also propose to augment the sample by 

interviewing the spouse/cohabitating romantic partner. These data will allow us to 

characterize the impact of marital and romantic relationships on health by examining the 

effects of one person’s characteristics and behaviors on the health of the other. We 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, we will explore our 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. 

Title: Menopausal Symptoms Initiative-Finding Lasting Answers for 

Sweats and Hot Flashes

P.I.: Andrea Z. LaCroix 

Institution: Fred Hutchinson Cancer Research Center 

Grant No.: AG032699-05

Award: $200,000
31

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. We 

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). Our 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. 

Title: The Role of Vascular Aging in Cognitive and Physical Function

P.I.: Lydia Bazzano 

Institution: Tulane University of Louisiana 

Grant No.: AG041200-01A1

Award: $300,000

Maintaining optimal health, both physical and cognitive, throughout the aging process is 

critical to minimizing healthcare costs and morbidity and mortality associated with 

diseases of aging. The integrity of the vascular system is essential for healthy aging. 

Aging-related structural and functional disturbances in the macro- or microcirculation 

contribute the development of cognitive dysfunction and declining physical performance. 

Early life factors, from birth through childhood and adolescence, may play an important 

role in successful cognitive and physical aging via the aging of the vascular system. In 

the proposed study we will examine the role of vascular aging in maintenance of 

cognitive and physical performance by recruiting 1,257 participants in the Bogalusa 

Heart Study cohort who participated in cardiovascular risk factors examinations at least 

twice in childhood and twice again in adulthood. Participants will undergo cognitive 
32

function testing, physical function assessments and vascular risk factor examination with 

noninvasive studies of vascular structure and function. Birth weight and childhood 

socioeconomic and risk factor data is available for all individuals. Longitudinal analysis 

will be used to examine the relationship of early life risk factrs to subclinical vascular 

disease markers, while linear models will be used to examine the role of vascular risk 

factors and subclinical markers in maintenance of cognitive and physical function. This 

study represents a unique opportunity because all vascular disease risk factors have been 

collected prospectively from early life to middle-age in this bi-racial (black/white), rural 

community, allowing for exploration of race and gender relationships with cognitive and 

physical function from mid-life. The proposed research will link vascular risk factors 

across the life span and subclinical vascular markers in early middle age with cognitive 

and physical performance in later middle age. In doing so, we will identify risk factors, 

timing and subpopulations for intervention that could reduce the incidence of cognitive 

and physical decline in old age and improve the rate of successful aging for persons 

across the nation. 

Title: Hypertension, Angiotensin Receptor Blockers, and Cognition: 

Effects and Mechanism

P.I.: Ihab M. Hajjar 

Institution: University of Southern California 

Grant No.: AG042127-01A1

Award: $200,000

Hypertension is associated with cognitive impairment even in the absence of dementia. 

These vascular-related mild cognitive impairments are undetected and are commonly 

characterized by executive dysfunction. To date, no specific treatment is available for 

executive mild cognitive impairment which is associated with poor outcomes in 

hypertension. The PI has recently completed, with support from a K23 award, a 

preparatory pilot study (n=47) to test the feasibility, safety and effect size of candesartan, 

an angiotensin receptor blocker, compared to hydrochlorothiazide and lisinopril, in 

individuals with hypertension and mild cognitive impairment characterized by executive 

dysfunction. Our preliminary analysis which was recently accepted for publication in the 

Archives of Internal Medicine, suggests that, independent of blood pressure, candesartan 

is superior to other antihypertensives in preserving executive function. Candesartan was 

also associated with an increase in cerebral blood flow velocity that only reached 

significance in those with low flow velocity at baseline (n=23). We hypothesized based 

on these data to further test the effect of angiotensin receptor blockers on cognitive 

function by conducting a 1-year double blind randomized active-control trial of 

candesartan vs. lisinopril in 160 individuals with hypertension and evidence of mild 

cognitive impairment in the executive domain. The specific aims of this proposal are to 

investigate the effects of candesartan on executive function decline and on change in 

cerebral perfusion, cerebrovascular reserve and microvascular brain injury. We also aim 

at Identifying potential underlying mechanisms related to vascular structure and function 

by which candesartan may affect the cognitive and cerebrovascular outcomes. 

Participants will be recruited from the greater Los Angeles Area and evaluated at the 
33

University of Southern California. Cognitive tests that assess executive function and 

other cognitive domains will be administered at baseline and 12 months after treatment. 

Neuroimaging which includes perfusion (continuous arterial spin labeling) and microstructure (diffusion tensor imaging), carotid ultrasound (carotid intima-media thickness), 

and endothelial and vascular inflammatory markers will be performed at baseline and 

after 12 months of treatment. This trial will shed more light onto the potential therapeutic 

effects of angiotensin receptor blockers on executive dysfunction and related vascular 

brain injury. This project will also improve our understanding of the possible 

mechanisms of action of this class of antihypertensives. 

National Institute on Alcohol Abuse and Alcoholism 

Title: Pharmacokinetics and Pharmacological Effects of Alcohol After 

Bariatric Surgery 

P.I.: Marta Yanina Pepino 

Institution: Washington University 

Grant No.: AA020018-01A1

Award: $258,709

Today, millions of Americans have had bariatric surgery, and given the magnitude of the 

obesity epidemic, it is anticipated that this number will continue to rise. Despite the 

numerous health benefits of these procedures, there is a growing concern with the 

development of alcohol problems after gastric bypass surgery. We believe that changes in 

alcohol pharmacokinetics and subjective responses to alcohol that occur as a result of the 

anatomical and physiological changes caused by upper gastrointestinal tract diversion 

might be an important mechanism responsible for the association between gastric bypass 

surgery and postoperative alcohol abuse. The current proposal will be the first study that 

will investigate the effects of gastric bypass surgery on subjective responses to alcohol 

and alcohol pharmacokinetic using validated methods and controlling for the important 

confounding effect of changes in body weight. Patients who will undergo gastric bypass 

surgery and a group of patients undergoing banding gastric surgery will be evaluated 3 

times before and 3 times 9 m after surgery following identical procedures. Unlike after 

gastric bypass, the anatomy of the intestine/stomach is intact after gastric banding. Thus, 

gastric banding subjects will allow controlling for changes in alcohol metabolism and 

mood effects that could be caused by weight loss. Breath and blood samples will be taken 

before and at various times after a dose of alcohol (0.8 or 1.4 g/l of total body water) or 

non-alcoholic placebo control are consumed. Blood alcohol concentrations (BAC) will be 

determined by the gold standard technique of headspace gas chromatography and these 

concentrations will be compared with the BAC estimated from breath samples. 

Subjective ratings of alcohol effects will be measured by validated questionnaires 

extensively used in the field. The results from our study will lay the foundation for 

understanding the effect of gastric bypass and gastric banding procedures on alcohol 

kinetics and pharmacodynamics, which can help tailor counseling in patients undergoing 

these procedures and prevent alcohol misuse after surgery.
34

Title: Ethanol-Induced Conditioned Partner Preference in Mice 

P.I.: Ruth I. Wood 

Institution: University of Southern California

Grant No.: AA020575-01A1

Award: $205,000

Drinking behavior and social context are intimately intertwined, particularly among 

young adults. Peer relations can promote drinking. At the same time, alcohol 

consumption promotes social bonding, as in the popular concept of a “drinking buddy”. 

Ultimately, to combat unhealthy patterns of social drinking, it is important to understand 

how ethanol shapes the neurochemistry of affiliative behavior. We have developed a 

mouse model of conditioned partner preference, and we have obtained pilot data to 

demonstrate ethanol (EtOH)-induced social preference in female mice. Conditioned 

partner preference is similar to conditioned place preference, but it incorporates social 

aspects of approach, recognition, and affiliation. This has relevance to drinking behavior 

in humans. In our pilot studies thus far, female mice prefer conspecifics with whom they 

have previously been intoxicated. There is a further interaction of EtOH and estradiol to 

promote social preference, since EtOH-induced partner preference is enhanced in 

estrogen-treated ovariectomized females (OVX+E) vs ovariectomized females without 

estrogen (OVX). The proposed studies will use C57Bl/6 female mice to extend our initial 

observations. Aim 1a will determine the range of EtOH doses which facilitate 

conditioned partner preference in OVX, OVX+E, and OVX+E females with 

progesterone. Aim 1b will examine sex differences in EtOH-induced conditioned partner 

preference by testing orchidectomized males with and without testosterone. Aim 2 will 

expand the conditioned partner preference model to test the effects of other drugs of 

abuse (amphetamines, morphine) on social bonding. Finally, Aim 3 will begin to explore 

underlying mechanisms for EtOH-induced conditioned partner preference. In this regard, 

pair bonding and affiliative behavior are sensitive to vasopressin mediated through the 

vasopressin V1a receptor. Furthermore, the vasopressin system is sensitive to both EtOH 

and estradiol. Aim 3 will test the ability of a V1a receptor antagonist to block EtOHinduced conditioned partner preference. Together, these studies represent an essential 

first-step to understand substance abuse and social bonding in mice.

Title: Role of MSK1, ERa and Brf1 in Alcohol-Associated Breast Cancer

P.I.: Shuping Zhong 

Institution: University of Southern California

Grant No.: AA021114-01A1

Award: $205,000

Alcohol is the dietary factor, which is most consistently associated with breast cancer 

risk. This association involves the estrogen receptor (ER), which is over-expressed (ER+) 

in around 80% of breast cancer cases. Alcohol-association is more pronounced in ER(+) 

breast cancer cases than in ER(-) breast cancer cases, however, the molecular mechanism 

remains to be determined. Cancer cells have a consistent cytological feature of nucleolar 
35

hypertrophy, where rRNAs are synthesized by RNA polymerases (Pol) I and Pol III. 

Pathologists have been using enlarged nucleoli as a diagnostic indicator of cell 

transformation and neoplasia. It indicates that transformation in situ is tightly linked to 

the deregulation of RNA Pol I and III gene transcription, because the size of the 

nucleolus reflects the levels of rRNA synthesis. RNA Pol III is responsible for the 

synthesis of a variety of untranslated RNAs, including 5S rRNAs and tRNAs. 

Deregulation of RNA Pol III-dependent genes (Pol III genes) would serve to enhance the 

translational capacity of cells, which is required to promote cell transformation and tumor 

development. Alcohol-induced deregulation of Pol III genes may be fundamental to the 

development of breast cancer. Our previous studies demonstrated that MAP kinases 

modulated Brf1 and TBP expression and Pol III gene transcription and mediated 

phosphorylation of histone H3 (H3ph). Our recent studies have demonstrated that ethanol 

activates MAP kinase and induces Pol III gene transcription through enhanced TBP and 

c-Jun expression by using cell culture and an animal model. Preliminary results have 

revealed that alcohol induces Pol III gene transcription in both normal breast and breast 

cancer cell lines. However, the induction in breast cancer cells (5-6 fold) is higher than i 

normal breast cells (2.5 fold). Further analysis indicates that the induction is ER 

dependent. The ER ligand, E2 (17b-estradiol) causes an induction (< 2 fold) of these 

genes, whereas ethanol works with E2 to create an additional increase (12 fold) in Pol III 

gene transcription, resulting i cell proliferation and transformation. Alcohol activated 

MSK1 (mitogen- and stress-activated protein kinase 1), a downstream component of 

MAP kinases, which mediates phosphorylation of histone H3 (H3ph) at serine 10 

(H3S10ph) and serine 28 (H3S28ph) and modulates gene expression and cell 

transformation. Thus, we hypothesize that alcohol activates MSK1, which mediates 

H3ph. H3ph in turn upregulates Brf1 expression and Pol III gene transcription to enhance 

the protein synthetic capacity of cells, which can eventually lead to ERa-dependent breast 

cancer. This implies that the induction by alcohol may be an early event, contributing to 

the development of ER(+) breast cancer. By using cell culture and animal models, we 

will determine: 1) if alcohol-activated MSK1 mediates Brf1 expression and Pol III gene 

transcription, which in turn causes phenotypic changes, and if inhibition of MSK1 by its 

chemical inhibitor and shRNA or using a MSK KO mouse blocks alcohol-induced cell 

transformation and Pol III gene transcription; 2) if alcohol-induced H3ph modulates Brf1 

and Pol III gene expression and cell transformation; 3) if alteration of ERa and Brf1 

expression affects transcription of Pol III genes and if blocking Brf1 expression by its 

shRNA inhibits tumor formation in nude mouse upon administration of alcohol or alcohol 

plus E2. These studies are designed to determine the molecular mechanism of alcoholinduced deregulation of Pol III genes in the development of ER+ breast cancer. 

Investigating the effects of MSK1 and Brf1 shRNAs on tumor formation may provide a 

new approach to inhibit tumor growth. Our overall objective is to investigate the role of

MSK1 and Brf1 in the alcohol-induced response that may be critically important in ER+ 

breast cancer development.

National Institute of Allergy and Infectious Diseases 

Title: Mechanisms of B Cell Responses in Autoimmune Disease
36

P.I.: Eugene William St. Clair

Institution: Duke University

Grant No.: AI056363-09

Award: $30,000

This application is a competitive renewal of the Autoimmunity Center of Excellence 

(ACE) at Duke. Its research focus will continue to be modulation of B cell responses in 

autoimmune disease. The ACE will be under the leadership of Dr. E. William St. Clair,

Professor of Medicine and Immunology. For the past 5 years, Duke has been a productive 

member of the ACE network, contributing new insights into the developmental pathways 

of B cells and the mechanisms of B cell directed therapy. The proposed ACE builds on 

these discoveries and will support 2 new basic science projects, 5 ongoing and 2 new 

clinical trials, and an Administrative Core, and continue to emphasize a strong and fluid 

integration between the bench and the bedside. Tedder and colleagues have recently 

found that a phenotypically unqiue subset of B cells secreting IL-10 (called B10 cells) 

serve as critical negative regulators during adaptive CD4+ T cells responses, and 

dramatically suppress Th1 immune responses and autoimmune disease in mice. For Basic 

Research Project 1, they will examine the hypothesis that antigen-specific regulatory B10 

cells modulate autoimmune responses in mice and man and that they can be manipulated 

for therapeutic gain. A picture is gradually emerging about the precursors of self-reactive 

B cells in autoimmune disease. Kelsoe and coworkers in Basic Research Project 2 will 

investigate developmentally regulated expression of activated cytidine deaminase (AID) 

in human fetal and neonatal pre-, pro, and immature/transitional B cells and its 

relationship to the generation of self-reactive B cells in human autoimmune disease, 

potentially eludidating another pathway of B cell self-reactivity outside the confines of 

normal tolerance mechanisms. We propose two new clinical trials to investigate 

lymphotoxin-beta receptor fusion protein as a treatment for primary Sjögren’s syndrome, 

and rituximab therapy for bullous pemphigoid. A Pilot Research Project is also proposed 

to engineer tetramers of self-antigen enabling the identification and characterization of 

self-reactive B cells, which will have implications for the goals of the clinical and other 

basic research projects. Overall, the Duke ACE will bridge these basic and clinical 

studies to advance our understanding of autoimmune disease. The B cell is a type of 

immune cell essential to autoimmunity. The goal of the proposed Autoimmunity Center 

of Excellence at Duke is to improve our understanding of the roles played by B cells in 

human autoimmune disease. The projects are designed to be highly integrative between 

the bench and the bedside, with collaborations between basic and clinical scientists. 

These studies may lead to better treatments. CLINICAL COMPONENT: Clinical 

Component (ST CLAIR, W) CLINICAL COMPONENT DESCRIPTION (provided by 

applicant): The Clinical Research Component of the Autoimmunity Center of Excellence 

shares with the Basic Research omponent an overall goal of advancing our understanding 

about the role of B cells in the pathogenesis of autoimmune diseases. This component 

will be directed by Dr. E. William St. Clair. During the past 5 years, the Duke ACE has 

brought 3 new clinical trial concepts to the ACE Steering Committee, resulting in 1 

completed trial, 1 ongoing trial, and 1 protocol in development. We are also participating 

in 3 other ongoing ACE-sponsored clinical trials. Therefore, substantial clinical research 

activity will carry over to the next funding cycle. Our center is organized to support 
37

clinical trials in rheumatology, dermatology, gastroenterology, hematology, and 

neurology. We have access to several large patient populations, including patiens with 

rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren’s syndrome, 

scleroderma, autoimmune blistering disease, psoriasis, inflammatory bowel disease, 

autoimmune hepatitis, anti-phospholipid antibody syndrome, and myasthenia gravis. 

Each of these disease areas has leadership from one or more physician-investigators with 

significant clinical trial experience, including an example of a productive interinstitutional collaboration. The physician leadership is supported by an ample 

infrastructure that provides clinical research space, infusion facilities, experienced 

clinical coordinators, and an Immune Monitoring Component. The Clinical Research 

Component aligns with the ACE at a thematic level, with substantial collaborations 

between basic and clinical scientists. To this end, the proposed clinical trial concepts will 

focus on B cell directed therapy. In one case, we propose to examine the clinical efficacy 

of lymphtoxin-beta receptor fusion protein in the treatment of primary Sjögren’s

syndrome, and have already secured commitment from the industry sponsor to provide 

study drug for this trial. The other application will investigate rituximab as initial therapy 

for bullous pemphigoid. The mechanistic studies for these proposed trials as well as 

current trials are highly integrated with the basic research projects. The Clinical Research 

Component will make a significant contribution to the ACE enterprise during the 

upcoming funding cycle. The Clinical Research Component will support clinical trials 

sponsored by the Autoimmunity Centers of Excellence in several disease areas, including 

rheumatology, dermatology, gastroenterology, hematology, and neurology. It has been 

productive during the current funding cycle, and has the capability, as shown in this 

application, to generate new ideas for clinical trials that can be translated into welldesigned studies.

Title: Epithelial Genes in Allergic Inflammation

P.I.: Gurjit K. Khurana Hershey 

Institution: Cincinnati Children’s Hospital Medical Center 

Grant No.: AI070235-07

Award: $12,500

Allergic disorders are a major global health concern affecting 150 million people 

worldwide. Recently, epithelial cells have emerged as central participants in the 

pathogenesis of allergic inflammation: (1) they interface with the environment and 

initiate the response to environmental triggers; (2) the mucosal epithelium in the lung, 

skin, and gut functions as a physical barrier against pathogens and environmental 

exposures including allergens; and (3) epithelial cells have been directly implicated in 

Th2 responses, serving as a critical interface between innate immune responses and Th2 

immunity. The overall objective of these studies is to elucidate the mechanisms by which 

epithelial cells contribute to the pathogenesis of allergic disorders. The overarching 

hypothesis of this Center proposal is that epithelial cell genes play a central role in the 

pathogenesis of allergic disorders. This hypothesis will be tested by three integrated 

projects that use the Center for coordination and synergistic extension of the projects 

beyond the scopes and capabilities of the individual projects. This Center will provide 
38

important insights into the genes and pathways that may be Important in epithelial driven 

allergic inflammation and provide a basis for the design of novel therapeutic strategies 

aimed at the epithelial surface, i.e. lung (asthma), skin (atopic dermatitis), or gut (food 

allergy or eosinophilic esophagitis). Furthermore, integration of data across projects will 

provide novel insights into a key question in allergy—What are the mechanisms 

underlying tissue specific disease manifestations of allergic inflammation? Each project 

in the Center is focused on distinct epithelial cell genes and their roles in allergic 

disorders. Project 1 will examine the association of epithelial genes with allergic diseases 

that target distinct mucosal surfaces. Project 2 will dissect the role of epithelial 

desmoglein-1 in the pathogenesis of the allergic disorder eosinophilic esophagitis. Project 

3 will focus on delineating the mechanisms by which epithelial-derived IL-33 is regulated 

by trefoil factor 2 (TFF2) during the early innate immune events that initiate allergy and 

asthma; and better define the role of the TFF2/IL-33 pathway in the pathogenesis of 

allergic disorders.

Title: Role of Unique ADP-Ribosylating Vacuolating Mycoplasma 

Pneumoniae Toxin in Asthma

P.I.: Joel Barry Baseman 

Institution: University of Texas Health Science Center at San Antonio 

Grant No.: AI070412-07

Award: $12,500

The San Antonio Asthma and Allergic Diseases Cooperative Research Center (SAAADCRC) represents a tightly focused, integrative and innovative effort to understand 

the role of Mycoplasma pneumoniae and its unique ADP-ribosylating and vacuolating 

toxin, designated Community Acquired Respiratory Distress Syndrome ToXin (CARDS 

TX) as important mediators of acute and chronic airway diseases, including new onset 

asthma and exacerbations, as well as persistent pulmonary dysfunction in children and 

adults. The basic science and clinical investigators who comprise the SA-AADCRC team 

share broad expertise and are highly collaborative. The SA-AADCRC’s broad strategy of 

attack interlinks basic science and clinical research projects and cores. Project 1 uses the 

murine model and human materials to address fundamental questions on how CARDS 

TX induces asthma-like disease and exacerbates allergic pulmonary inflammation. 

Project 2 focuses on identifying CARDS TX ADP-ribosylating airway protein targets, 

delineating functionally important CARDS TX domains and essential amino acids that 

mediate CARDS TX binding to human surfactant protein A (SP-A) and airway cells, and 

generating antibody reagents that block/neutralize CARDS TX. Project 3 applies state-ofthe-art biophysical techniques to uncover the structure and action of CARDS TX by 

using single crystal X-ray diffraction to determine CARDS TX three dimensional 

structure in the presence and absence of its cofactor NAD; neutralizing monoclonal 

antibody Fab fragments; and surfactant protein-A (SP-A). Clinical Core will collect 

human material from subjects with well controlled asthma, poorly controlled asthma and 

healthy controls and help in evaluation and follow-up of patient-related studies. 

Diagnostic Core will process clinical and experimental samples for diagnostic analysis by 

providing highly sensitive and specific diagnostic assays for rapid detection of M. 
39

pneumoniae CARDS TX. Pathology Core will provide necessary biopsy and necropsy 

procedures, lung pathology interpretation, histochemical and immunocytochemical 

evaluations, and qualitative and semiquantitative histopathologicai analyses. 

Administrative Core will oversee all SA-AADCRC-related activities and coordinate 

interactions and collaborations between projects and cores. Therefore, the SA-AADCRC 

represents a network of collaborators/colleagues who continuously ask fundamental and 

translational questions about asthma, airway-related pathologies, immunopathogenesis, 

and M. pneumoniae/CARDS TX biology and virulence mechanisms.

Title: Epithelial Barrier Programs in Asthma and Allergic Disease

P.I.: Michael J. Holtzman 

Institution: Washington University 

Grant No.: AI070489-07

Award: $12,500

The overall goal of this AADCRC proposal is to define the role of the epithelial cell 

barrier in the pathogenesis of asthma and allergic disease and to use that information to 

prevent this type of disease. We combine expertise in airway as well as gut and skin 

epithelial cell biology, and we use cell and mouse models with high fidelity to directly 

translate our findings to humans. The AADRC therefore consists of three interrelated 

Projects that ask, first, how airway epithelial cells mediate effective antiviral defense 

under one condition but asthma under another (Project 1), second, how airway epithelial 

cells remodel towards an overabundance of mucous cells in post-viral and allergic asthma 

(Project 2), and third, how epithelial injury in the skin triggers the march from atopic 

dermatitis to asthma (Project 3). Each project addresses the respective question with a 

novel but overlapping molecular approach to mechanism and takes advantage of a 

breakthrough discovery to set a new scientific paradigm for the system under study. 

Thus, Project 1 unravels a new IFN signaling pathway that offers improved protection 

against viral infection and post-viral asthma and is specific to the airway epithelial cell 

barrier; Project 2 dissects a new pathway for autophagy proteins to support proper 

mucous cell function and prevent mucous cell metaplasia in the airway in a manner 

reminiscent of the intestinal epithelial barrier; and Project 3 defines a new TSLP 

production and secretion pathway that drives airway inflammation based on its 

expression in the skin epithelial barrier. Each Project is constructed so that the first aim 

will establish a basic pathogenic mechanism using cell and mouse models that are shared 

among projects and supported by the Cores for tissue and cell processing (Core C) and 

mouse models (Core D). In turn, each Project will conduct a second aim to validate and 

translate its findings using samples from children and adults with asthma and/or atopic 

dermatitis supplied by the Core for human subjects and data analysis (Core B). Sharing 

samples and overlapping scientific goals among projects create a synergistic program that 

can be coordinated by a common Administrative Core (Core A). Project and Core 

interactions are based on the overall principle that each Project begins with molecular 

hypothesis building in cell and mouse models and translates findings from these models 

to studies of humans with asthma and/or allergy. In each project, we aim to validate a 

clinically useful biomarker of the disease process and lay the groundwork for the future 
40

development of biological and/or small molecular weight compounds that might 

influence the process as a therapeutic strategy.

Title: Airway Inflammation and Airway Remodeling

P.I.: David H. Broide 

Institution: University of California at San Diego 

Grant No.: AI070535-07

Award: $12,500

Airway remodeling is the term applied to the structural changes observed in the airway in 

asthma. Although current NIH guidelines recommend maintaining a goal of normal lung 

function in asthma, current therapeutic strategies do not specifically target airway 

remodeling as the cellular and molecular mechanisms that result in remodeling are not 

well defined and thus therapeutic targets are not well understood. Thus, there is an 

important need to identify mechanisms by which airway remodeling is mediated so that 

potential novel therapies could be directed at these pathways. In addition, 

characterization of these pathways could lead to the development of non-invasive blood 

or sputum biomarkers to identify, monitor, and perhaps subset, patients with asthma and 

remodeled airways. This UCSD AADCRC proposal will be directed by David Broide 

(Professor of Medicine) and include three projects (Broide, Croft, Zuraw) that will 

investigate mechanisms of airway remodeling in asthmatics exposed to allergen and 

rhinovirus common triggers of asthma. Thus, the overall hypothesis that will be explored 

in all three projects is that exposure to allergen triggers expression of inflammatory and 

remodeling pathways in allergic asthmatics that are exacerbated by exposure to 

respiratory viruses such as rhinovirus. The specific hypothesis that will be explored in 

each project and that will be driven by samples from asthmatics, is that the innate 

immune response (airway epithelium, macrophages, natural helper cells) play an 

important role in initiating and perpetuating the inflammatory and airway remodeling 

response to environmental triggers in allergic asthmatics. The three interrelated projects 

will focus on Innate inflammation and airway remodeling (Broide, Project 1), TNF-R 

family members, inflammation and remodeling (Croft, Project 2), and Epithelial GILZ 

inflammation and remodeling (Zuraw, Project 3) and be supported by Administrative

Core A, and Asthma Clinical Core B, which will be a source of sputum, BAL, 

endobronchial biopsy, and blood samples from asthma and control subjects provided by 

investigators in Core B (Ramsdell, Harrell, and Thistlethwaite, UCSD; Proud and Leigh, 

University of Calgary; and Hamid, McGill University). An lOFM Core is also proposed 

as requested by the RFA.

Title: Oklahoma Autoimmunity Center of Excellence

P.I.: Judith A. James 

Institution: Oklahoma Medical Research Foundation 

Grant No.: AI082714-04

Award: $30,000
41

The Oklahoma Medical Research Foundation is home to outstanding clinical and basic 

science investigators who have research interests in the etiology and pathogenesis of 

autoimmune diseases and seek to identify novel therapeutics for more effective patient 

treatments. The scientific expertise, extensive clinical trial experience, access to 

geographically distinct patient populations, as well as unique patient registries, 

repositories and core technologies provide a solid foundation for the Oklahoma 

Autoimmunity Center of Excellence (ACE) application to which we have added a 

multidisciplinary team of clinical and basic science investigators. The focus of the 

Oklahoma ACE application is on expediting the translation of scientific discoveries in 

autoimmunity to clinical application in the diagnosis and treatment of systemic 

autoimmune diseases. To accomplish this, the Oklahoma ACE comprises two research 

projects, a proposed pilot research project, a Clinical Center (Joan Merrill, PI) and an 

administrative core (Judith James, PI). The research projects focus on thrombotic 

thrombocytopenic purpura, systemic lupus erythematosus, and Sjögren’s syndrome, 

which are also focuses of the Clinical Center. Multiple sclerosis, rheumatoid arthritis, 

pediatric arthritis, insulin-dependent diabetes, idiopathic thrombocytopenia and pediatric 

lupus are other key disease emphases of the Clinical Center. Two complimentary, but 

unique, research projects focus on understanding early events in the development of 

lupus autoimmunity and in defining targetable genetic associations in Sjögren’s

syndrome. The pilot project uses complimentary methods to address roles of elevated 

interferon activity in patients with TTP and a novel animal model of thrombocytopenia. 

In addition, two clinical trials are proposed; both of which enhance or build upon the 

basic science projects. The first studies efficacy and mechanistic affects of anti-IFN in 

select SLE patient subsets by applying a patient centric, dose optimization strategy. The 

second tests the efficacy and early MRI changes of a novel MEK1/MEK2 inhibitor in RA 

with additional mechanistic studies. The Administrative Core will provide leadership and 

management through acting on behalf of the Oklahoma ACE members within the ACE 

Network and NIH Program, ensuring fiscal responsibility for the ACE, and providing an 

educational foundation for a multi-disciplinary approach to autoimmune disease research. 

Thus, the Oklahoma ACE will unite Oklahoma-based clinical and basic science experts 

to facilitate access to unique patient populations for participation in clinical trials and to 

understand basic mechanisms of etiology and pathogenesis. The Oklahoma ACE brings 

together adult and pediatric rheumatologists, neurologists, endocrinologists, 

dermatologists, hematologists, dentists, ophthalmologists, geneticists, immunologists, 

molecular biologists, epidemiologists and biostatisticians to provide a multidisciplinary 

approach to discovering and applying novel therapeutics in systemic autoimmune 

diseases. Through strong basic science projects paired with clinical expertise the 

Oklahoma ACE will provide unique research and clinical opportunities to the ACE 

Network. CLINICAL COMPONENT: CLINICAL CENTER (Merrill, J) CLINICAL 

COMPONENT DESCRIPTION (provided by applicant): The Oklahoma ACE Clinical 

Center brings together disease-specific and interdisciplinary clinics in systemic lupus 

erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren’s syndrome, thrombotic 

thrombocytopenic purpura, insulin dependent diabetes mellitus, pediatric SLE and 

juvenile inflammatory arthritis to forward translational research in autoimmunity. 

Patients from each of these disease populations are available and committed to participate 

in potential national ACE investigations. With adult and pediatric rheumatologists, adult 
42

and pediatric endocrinologists, neurologists, hematologists, dermatologists, 

ophthalmologists and dentists, as well as basic scientists from various areas of 

immunology, molecular biology, genetics, epidemiology and biostatistics, our 

investigative team is poised to make basic advances regarding disease pathogenesis and 

to help translate these discoveries to the clinic. The Clinical Pharmacology program at 

OMRF will serve as the primary home for the SLE, RA, Sjögren’s syndrome and TTP 

clinics. Currently leading or participating in more than 20 active clinical trials, this 

clinical center is accustomed to participating in clinical trials, managing confidential 

patient information, and providing multidisciplinary care. In addition, the Clinical 

Pharmacology space provides investigators access to state-of-the-art research tools 

directly adjacent to the patient care unit. Pediatric IDDM and rheumatology clinics are 

housed across the street at OUHSC and a large, community based multiple sclerosis 

clinic will participate for MS patient investigation. Joan Merrill, MD serves as the leader 

of our Clinical Center. She is the current medical director of the Lupus Foundation of 

America and a leader in SLE clinical trial development. She has served as the lead 

investigator on large, multi-site trials. Combining her extensive knowledge of clinical 

trial design and the known heterogenic presentation of SLE, she proposes to devise 

patient-centric clinical trials that use biomarkers of disease to optimize therapeutic doses. 

Our Clinical Center proposes two potential clinical concepts. Based upon our basic 

science investigation regarding pivotal roles for increased interferon activity in preclinical SLE, Sjögren’s syndrome and potentially TTP, our first trial examines the 

efficacy and biologic impact of anti-INF alpha in SLE patients with arthritis and select 

dermatologic manifestations. The second trial proposes use of a first-in-class target of 

MEK1/MEK2 inhibition in RA to assess impact on MRI progression of disease and on 

select biomarkers. Both of these trials have mechanistic studies proposed to address key 

scientific questions regarding pathogenesis and response. The Oklahoma Autoimmunity 

Center of Excellence Clinical Center will provide interdisciplinary investigators with 

unique populations of well-characterized patients to participate in ACE network 

autoimmune disease clinical trials. With our rich Native American heritage and large 

rural populations, the patients provided by the Oklahoma ACE will be previously 

understudied and provide unique insights for therapeutic trials.

Title: A Systems Biology Approach for Pediatric and Adult Autoimmune 

Diseases

P.I.: Maria Virginia Pascual 

Institution: Baylor Research Institute 

Grant No.: AI082715-04

Award: $30,000

We propose to create an Autoimmunity Center of Excellence that will incorporate the 

efforts of clinicians, human immunologists (both basic and translational), physicianscientists with clinical expertise and research experience in autoimmunity, 

bioinformaticians, and geriomics/systems biologists. Together, the assembled group has 

an extensive background in clinical trials and a proven track record for merging basic and 

clinical science. This team is committed to bringing innovative treatments from the 
43

laboratory bench to their patients’ bedside. Within this collaborative setting, a systems 

biology approach is proposed to focus on both pediatric and adult autoimmune diseases.

The goals of the Center are: 1) To assess the efficacy of novel targeted therapies, 2) To 

develop simple and robust biomarkers using state-of-the-art genomic approaches, 3) To 

understand the role of recently identified T cell subsets in disease pathogenesis, and 4) To 

assess antigen-specific responses in pediatric and adult autoimmune diseases. These 

projects will provide a better understanding of the pathogenesis of specific autoimmune 

diseases and allow us to develop a strategy to assess disease activity based on novel 

transcriptional markers as well as to identify autoantigen-specific immune responses. The 

Center will deliver: 1) Innovative clinical trials targeting specific cytokines in psoriasis & 

dermatomyositis. 2) Development of biomarkers for dermatomyositis, psoriasis, lupus 

and multiple sclerosis. 3) Identification of novel therapeutic targets in dermatomyositis.

4) Development of assays to test autoantigen-specific immune responses. 5) 

Development of a unique microarray database of human autoimmune diseases.

CLINICAL COMPONENT (Cush, J) CLINICAL COMPONENT DESCRIPTION 

(provided by applicant): Baylor Institute for Immunology Research aims to bring together 

a distinguished team of clinical investigators to conduct cutting-edge clinical trials on 

specific autoimmune diseases. This unique group of investigators and clinicians has 

appointments at Baylor University Medical Center, UT Southwestern Medical Center, 

Texas Scottish Rite Hospital in Dallas and Northwestern University. These talented 

individuals have been enlisted from diverse programs with subspecialties in dermatology, 

rheumatology, neurology, pediatrics, and human immunology. They provide a set of 

inimitable resources for clinical trials and have a proven track record for merging basic 

and clinical science. Indeed, this team is committed to bringing innovative treatments 

from the laboratory bench to their patients’ bedside. With such outstanding collaborative 

players, a systems biology approach is proposed here which investigates both pediatric 

and adult autoimmune disease. To this end, two Phase II randomized, double-blind, 

placebo-phase controlled clinical trials are proposed. The first trial investigates whether 

blocking IL-1 with Anakinra will result in objective disease improvement for patients 

with Juvenile Dermatomysitis. The trial design will demonstrate: 1) if the time to 

improvement for patients receiving Anakinra early in the study will be earlier than those 

who receive later treatment; and 2) if the proportion of patients improved at week 8 of the 

blinded phase will be significantly greater in the early treatment group. Mechanistic 

studies will utilize gene expression profiling assays to find a novel diagnostic test for 

JDM as well as disease activity measures and biomarkers to follow and predict patients’

response to therapy. The second clinical project proposes to use a-IL-17 in patients with 

plaque psoriasis as well as psoriatic arthritis. Specifically, this study will assess the safety 

and efficacy of a-IL-17 in these patients and determine both the time to achieve endpoints 

of a PASI 75 or ACR20 and sustainability of such responses at 24 weeks. Associated 

studies will establish blood transcriptional markers to predict clinical responses in 

patients treated with a-IL-17, determine if transcriptional scores can be used to assess 

disease activity, and analyze the effect(s) of IL-17 blockade on B and T cell subsets. A 

dynamic team of clinical investigators assembled at BUR to conduct state-of-the-art 

clinical trials on autoimmune disease would be of great value and accelerate the process 

of bringing research from the laboratory bench to the bedside. This team proposes two 
44

important trials that will assess a-IL-1 treatment in Juvenile Dermatomyositis and IL-17 

blockade in psoriatic diseases.

Title: Autoimmunity Center of Excellence (ACE) at Stanford

P.I.: Charles Garrison Fathman 

Institution: Stanford University 

Grant No.: AI082719-04

Award: $30,000

The Stanford ACE will support an integrated basic and clinical research program focused 

on tolerance induction and immune modulation to prevent or treat autoimmune disease. 

The major theme of the Stanford Autoimmunity Center of Excellence (the Center) is the 

study of the regulation of CD4 T cells in pathogenesis and treatment of autoimmune 

diseases. The Center will support and be supported by other ACE groups across the 

United States; and will take advantage of Stanford’s documented leadership in basic and 

clinical research, technology development, and education in clinical immunology. 

Success of the Center will be supported by the interrelationships previously established at 

Stanford among clinician scientists from multiple departments studying autoimmune 

diseases in multiple organs and tissues. The Stanford ACE will be composed of 

outstanding basic and clinical investigators from multiple disciplines at Stanford Medical 

School and proposes both a basic Research Project, centered on CD4 T cell 

unresponsiveness, and a translational Research Project to study a new T cell lineage 

(termed Th17 cells) that is characterized by the ability of these lymphocytes to secrete 

high levels of the proinflammatory cytokine interleukin-17 (IL-17). Proposed clinical 

research projects encompass three different autoimmune diseases [diffuse systemic 

sclerosis (SSc), psoriatic arthritis and systemic juvenile idiopathic arthritis (SJIA)] that 

afflict adults and children, as well as organ systems including joints, skin, blood 

elements, and blood vessels, and will both test efficacy of therapy and develop tests to 

characterize the mechanisms of action of these therapeutics. The proposed Pilot and 

Feasibility Project proposes a two year research plan in Systemic Juvenile Idiopathic 

Arthritis (SJIA) patients to identify and validate urine peptide biomarkers that predict (a) 

response to TNF inhibition; (b) response to IL-1 inhibition; and (c) impending disease 

flare. In addition, this proposal will provide other ACE groups access to cutting edge 

reagents and technology platforms for studying human autoimmune diseases, and 

dissemination of Educational Materials that can be used by other ACEs to teach clinical 

immunology concepts to high school, undergraduate, graduate, postgraduate, and clinical 

fellows and faculty. The Stanford ACE proposes to support integrated basic, pre-clinical 

and clinical research by proposing and then conducting basic and translational research 

into the mechanism of CD4 T cell unresponsiveness; two clinical trials that include novel 

therapies and mechanistic studies of these therapies for autoimmune diseases; and a pilot 

proposal that intends to develop new bi omarkers of disease. PROJECT 1A: Clinical 

Component (Genovese, M) CLINICAL COMPONENT DESCRIPTION (provided by 

applicant): Stanford University Medical Center (SUMC) has an extraordinary tradition of 

medical, translational, and basic science research. An outstanding array of resources, 

faculty, and facilities will be available to support the proposed ACE site at Stanford 
45

University. This proposal brings together a skilled group of translational researchers with 

a track record of productivity in both laboratory and clinical research focusing on human 

autoimmune mediated diseases. Stanford has brought together various disciplines to 

demonstrate both accomplishment and ability to work together with the following fields 

represented: Adult Rheumatology, Dermatology, Pulmonary Medicine, and Pediatric 

Rheumatology. The projects chosen for this submission highlight the significant 

collaborations that exist between Rheumatology (Adult and Pediatric), Dermatology and 

Pulmonary Medicine. Both clinical trials projects explore dermatologic and 

rheumatologic manifestations of diseases such as Psoriatic arthritis and Systemic 

Sclerosis. Clinical Trial Concept 1: The use of an anti-IL-17 mab in the treatment of 

active Psoriatic Arthritis Primary Hypothesis: The proportion of patients achieving the 

ACR 20 response from Baseline to Week 14 among active Psoriatic Arthritis (PSA) 

subjects treated with IL-17 mab is larger than the proportion achieving ACR 20 response 

from Baseline to Week 14 among active PSA subjects treated with placebo Objectives: 

The goal of this study is to determine the safety and efficacy of a monoclonal antibody to 

lnterleukin-17 (IL-17 mab) in the treatment of PsA with active skin and joint disease. 

Clinical Trial Concept 2: The use of CTLA-4lg (abatacept) in subjects with diffuse 

systemic sclerosis Primary hypothesis: Given several lines of evidence supporting the 

role of activated T cells in affected skin, we hypothesize that inhibiting T cell activation 

may lead to significant clinical improvement in skin manifestations in patients with 

diffuse systemic sclerosis (dSSc), and that changes in tissue and blood autoantibody and 

cytokine profiles will be associated with clinical response. Objectives: The primary goal 

of this study is to determine the safety and efficacy of CTLA-4lg (Abatacept) for the 

treatment of cutaneous manifestations of dSSc RELEVANCE (See instructions): The 

Stanford ACE will support an integrated basic and clinical research program focused on 

tolerance induction and immune modulation to prevent or treat autoimmune (Al) disease. 

The Stanford ACE proposes clinical research projects that encompass three different 

autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA 

of therapeutics for preventing or treating different Al diseases.

Title: Nanoparticle Microbicides for Delivery of Combination 

Antiretroviral Drugs

P.I.: Kim A. Woodrow 

Institution: University of Washington 

Grant No.: AI094412-02

Award: $18,750

Sexual transmission through the genital tract or rectal mucosa is the most common route 

for acquiring new HIV infections and accounted for ~70% of the 2.7 million people 

worldwide who became newly infected in 2007. A cure or effective vaccine that would 

contain the global spread of this epidemic is not expected in the near term, and new HIV 

infections continue to outpace advances made in treatment with antiretroviral drugs. 

There is consequently an urgent need to develop agents that can be applied topically to 

mucosal surfaces to prevent the sexual transmission of HIV. However, several large-scale 

clinical trials testing the efficacy of agents that disrupt the integrity of the viral envelope 
46

(detergents) or prevent adsorption or fusion of the virus with its target cells (polyanions) 

have failed to protect against HIV infection. The success of highly active antiretroviral 

therapy (HAART) provides a paradigm for developing the next generation of 

microbicides, raising the possibility that a combination of potent and broadly active 

inhibitors that exhibit multiple and complementary mechanisms of action may be vastly 

superior to the delivery of single compounds. To fully realize the potential of these potent 

antiretroviral (ARV) drugs, the challenges of formulating and delivering compounds with 

markedly different chemical stability and aqueous solubility in a topical combination 

product must be overcome. This research plan is designed to evaluate nanoparticle-based 

vaginal drug delivery systems for HIV prevention. The experimental focus is to achieve 

protection against vaginal transmission of HIV-1 by topical delivery of a combination of 

antiretroviral drugs using mucus- and tissue-diffusing nanoparticle microbicides. This 

research would be the first to control the temporal and spatial co-delivery of a 

combination of antiretroviral agents that have different mechanisms of action against 

HIV-1 (Aim 1). If successful, our studies would be the first to determine the size range 

and penetration depth accessible for nanoparticulate drug delivery systems in the vaginal 

mucosa (Aim 2). Our proposed research will also provide valuable data on the transport, 

biodistribution, and pharmacokinetics of encapsulated and released antiretroviral agents 

that are administered topically to the vaginal mucosa using nanoparticle microbicides 

(Aim 3). Finally, we will conduct preclinical safety and anti-HIV efficacy studies to 

rapidly advance our nanoparticle-based microbicides to human safety and efficacy trials 

(Aim 4). The outcomes from our proposed research may highly impact the field of 

microbicide research for HIV and other sexually-transmitted infections.

Title: Thermostable Vaginal Probiotic Microbicide

P.I.: Victor Bronshtein 

Institution: Universal Stabilization Technologies, Inc. 

Grant No.: AI094508-02

Award: $18,375

Recently revised statistics show the number of individuals living with HIV at over 33 

million worldwide, with 68% being in sub-Saharan Africa. Current HIV prevention 

methods, such as condom use, monogamy and abstinence, are not always feasible. The 

need for improved HIV preventative technologies remains urgent. The development of 

topical microbicides represents a new and exciting field in the prevention of sexually 

transmitted diseases. Of these, application of live probiotic bacterial microbicides (PBM) 

represents a promising preventative method. Our ultimate goal is to develop potent 

optimized multistrain thermostable and easily deliverable probiotic vaginal topical 

microbicides. To achieve this goal we will stabilize vaginal probiotics for long-term 

storage at high ambient temperatures and short term survival at temperatures required for 

quick dissolve film manufacturing (60¿C and above). The cornerstones of this proposal 

are: 1) Preservation by Vaporization (PBV)—an innovative, patent pending method of 

dry-stabilizing probiotics bacteria and other fragile biologicals at high ambient 

temperatures, and 2) Quick-dissolve thin film technology that is being optimized to 

deliver conventional vaginal microbicides. The strategy can be described briefly as, to 
47

occupy the vaginal epithelium and provide a long lasting protective environment against 

HIV, BV, and STI acquisition small (10-50 ¿m) glassy sugar particles containing PBV 

vaginal probiotic bacteria will be formulated into thin films which utilize a water soluble 

polymer base. Thin films offer a unique delivery platform which has a number of 

advantages over other dosage forms. In a recent study comparing women’s preference 

between films, tablets and ovules, the film dosage form was shown to have greatest 

acceptability among women studied. We believe that women will prefer using a vaginal 

film over other potential methods of probiotic microbicide delivery especially if a longacting effect of the bacteria colonizing vaginal epithelium allows for less frequent use. 

Biologic properties of PBM after long-term storage at ambient temperatures will be 

characterized using cell culture models of vaginal and cervical epithelium.

Title: The Semen Enhancer of HIV Infection as a Novel Microbicide 

Target

P.I.: Stephen Dewhurst 

Institution: University of Rochester 

Grant No.: AI094511-02

Award: $18,750

We will also test whether our lead molecules have efficacy in a cervical explant model 

for HIV-1 infection, and whether they have a synergistic or additive effect on the ability 

of other candidate microbicides to inhibit HIV-1 infection in the presence of semen. In 

the final Aim, we will assess the toxicity and inflammatory effects of the most promising 

candidate molecules, using beneficial Lactobacillus strains and cervical explants. The 

R33 phase will culminate with an evaluation of the safety and tolerability of the most 

promising compound in the rabbit vaginal irritation (RVI) model. The overall goal of 

these studies is to carefully determine whether small molecules that target SEVI have 

potential utility as a novel class of microbicides.

Title: Designing Optimal Microbicide Delivery Integrating Rheology 

and Acceptability

P.I.: John Edward Hayes 

Institution: Pennsylvania State University 

Grant No.: AI094514-02

Award: $18,750

This year perhaps 2.5 million people will be added to the approximately 35 million 

already infected with HIV/AIDS, 50% of whom are women. Topical microbicides offer 

these women a means to prevent sexually transmitted infections (STIs), including HIV. 

However, in addition to concerns about the biological efficacy of current microbicides, 

user acceptance of and adherence to their use is suboptimal. It has been estimated that a 

single microbicide with even limited efficacy could prevent millions of new HIV cases 

annually. The design of vaginal microbicide dosage forms has challenged formulation 

scientists. Safe and efficacious products are necessary, but not sufficient to assure 
48

adherence. User acceptability depends both on the physical properties of the material and 

behavioral factors. Constraints that drive acceptance must be identified and addressed 

early in development. The acceptability of the product to women must be evaluated 

preclinically. We propose the rational preclinical design and development of a dosage 

form that delivers an immediate efficacious dose of active pharmaceutical ingredient 

(API) followed by the slow release of API over a period of 1-3 days to maintain efficacy. 

This dosage form can be thought of as a temporal vaginal ring/diaphragm that releases 

API(s) as it slowly erodes away. These products will be an adaptation of current softgel 

capsule technology. However, unlike current gelatin capsules, we will develop a range of 

non-gelatin capsules varying in shape and firmness (texture). Human perceptual data will 

be assessed throughout and guide the design process. Carrageenan will be used for the 

development of heat-stable softgels that, unlike current gelatin capsules, will not melt in 

tropical environments. The two-phase nature of softgels (‘ovules’) will permit the 

inclusion of a second component. Our R21 goals provide for proof-of-concept of this new 

delivery system, and the R33 goals will optimize both acceptability and biophysical 

functionality. The R33 will also explore potential higher-order functionality, like 

mucoadhesion or delivery of probiotics. Here, we propose a new microbicide delivery 

system, designed to overcome both biological (insufficient HIV neutralization) and 

behavioral (poor acceptability and adherence) deficiencies of current products. By 

designing formulations that function for optimal efficacy and optimal use (acceptability / 

adherence), microbicides produced via these methods are likely to have a greater impact 

on the HIV/AIDS pandemic than those currently in the development pipeline. Also, by 

developing a methodology for design of vaginal products where multiple factors (shape, 

texture, size, and multi-stage delivery) play a central role, we increase the options women 

have in microbicide use. Critically, our product type is flexible—allowing for multiple 

textures, sizes, shapes and antiviral strategies—to accommodate a range of user 

preferences.

Title: Mucosal Tissue Explants as Surrogates for in vivo Efficacy of 

Microbicides

P.I.: Carolina Herrera 

Institution: University of London, Imperial College of Science, Technology 

and Medicine

Grant No.: AI094515-03

Award: $18,750

The HIV microbicide field is dependent upon testing in non-human primates (NHPs) as 

the only relevant model to study infection. However, the predictive accuracy of NHP 

studies of efficacy in humans has not been validated and as such the economic value is 

unknown. Hence, refinement of this model and development of a novel correlate of 

efficacy in humans that will reduce the potential use of NHPs is key for the global 

progress of microbicides and specifically of the Microbicide Innovation Program’s 

mission. This proposal addresses these issues by testing the hypothesis that ex vivo tissue 

explant cultures can provide a potential surrogate of in vivo efficacy through 

measurement of intra-tissular drug pharmacology and ex vivo infection/protection. This 
49

will be investigated using combined expertise in modeling mucosal tissue infection and 

measurement of antiretroviral (ARV) drug pharmacokinetics and pharmacodynamics in 

tissue. The proposal will focus on a reverse transcriptase inhibitor, PMPA (tenofovir), 

and an entry inhibitor, maraviroc, used alone and in combination as candidate 

microbicides. In the R21 component of the proposal we will demonstrate the robustness 

of our ex vivo explant models for analysis of pharmacological parameters and ex vivo 

infection independently of the origin (human or NHP) and the type of mucosa 

(cervicovaginal or colorectal). This will be investigated through two Specific Aims: 1) to 

define ex vivo pharmacological dose-responses (pharmacokinetics and 

pharmacodynamics) in human and rhesus macaque mucosal tissue explants; 2) to define 

whether the viral backbone affects pharmacological correlates of activity. The next step 

of our proposal in the R33 component will involve validation of the model as a surrogate 

for prediction of in vivo efficacy of ARV drugs as vaginal and colorectal microbicides. 

Here the two Specific Aims are: 3) to assess whether activity of drugs titrated in vivo can 

be predicted with ex vivo challenge models: 4) to correlate ex vivo and in vivo protection 

and drug dosing in NHPs. The iterative design of the overall proposal will allow us to 

assess correlates between intra-tissular pharmacological dosing and efficacy at all levels: 

tissue type, origin of tissue, route of dosing and challenge, and nature of experiment (ex 

vivo, in vivo). These correlates will define conversion factors of microbicides efficacy 

between the NHP model and in humans, which will be key for the rational development 

of existing and future candidate microbicides.

Title: Mucus Penetrating Particles for Rectal Microbicides

P.I.: Justin S. Hanes 

Institution: Johns Hopkins University 

Grant No.: AI094519-02

Award: $18,750

For reliable protection against STD transmission, rectal microbicides must be formulated 

in a way that will deliver the active agent to all the surfaces that are susceptible to 

infection. These include the entire rectum as well as a large fraction of the colon (due to 

peristaltic stirring of colonic contents). Colorectal surfaces are columnar epithelia that are 

mechanically and osmotically fragile, and are highly susceptible to STD transmission. 

Although continuous mucus secretion by these susceptible surfaces helps protect against 

trauma and pathogens, this continuously secreted mucus also poses a significant barrier 

against effective delivery of microbicides to the epithelial surface. Recently we 

developed novel mucus penetrating nanoparticles (MPP) that can overcome this barrier 

and provide sustained, well-distributed delivery of drugs to mucosal surfaces. Our 

hypothesis is that MPP will significantly increase the protective efficacy of rectal 

microbicides by achieving more uniform and complete colorectal distribution, sustained 

drug activity, and thus longer duration and more complete protection compared to drug 

delivered in gels (free drug) or drug delivered in conventional nanoparticles, CP, that

adhere to mucus and fail to penetrate mucus barriers. In the R21 phase, we will determine 

optimal MPP properties for penetration of mouse colorectal mucus, and we will 

characterize the uniformity of MPP distribution and retention times in the mouse 
50

colorectum compared to CP and free drug. We will then prepare drug-loaded 

biodegradable and biocompatible MPP that provide sustained release of antiviral drugs 

(valacyclovir for HSV and UC-781 for HIV). We will deliver these MPP in both a rectal 

enema format and a rectal lubricant gel format since both formats are frequently used for 

enhancing rectal intercourse. Moreover, an enema may deliver MPP to large regions of 

the colon unlikely to be reached by a gel. The key milestone for the R21 phase will be 

development of valacyclovir-MPP and UC-781- MPP that provide more complete and 

persistent coverage of the rectal epithelial surface, with minimal toxicity, compared to CP 

formulations or free drug. In the R33 phase, we will extensively test these MPP 

formulations for safety and protective efficacy in our mouse/HSV rectal model and in the 

hu-BLT-SCID mouse/HIV model (via a subcontract with Dr. J. Victor Garcia-Martinez at 

UNC).

Title: Development of an HIV-1 Entry Inhibitor Pre-drug as a 

Microbicide

P.I.: Min Lu

Institution: University of Medicine and Dentistry of New Jersey, Robert Wood 

Johnson Medical School

Grant No.: AI094555-02

Award: $18,750

With no vaccine in sight, there is an urgent public health need to develop an effective 

topical microbicide that can reduce the number of new HIV-1 infections in women. The 

potential role of virus-cell fusion inhibitor-based microbicides in preventing mucosal 

transmission of HIV-1 has been clearly identified. However, none of the reported gp41 

fusion inhibitors has made significant progress toward clinical trials. HIV-1 infection 

requires fusion of the viral and cellular membranes, driven by association of two heptadrepeat regions in the gp41 ectodomain to form a highly stable six-helix bundle structure. 

Whereas this postfusion motif comprising native N36 and C34 peptides has no inhibitory 

activity, the isolated peptides inhibit HIV-1 entry by binding to their cognate sites on 

gp41. Our goal in this MIP VI application is to develop an inexpensive, potent, structured 

‘pro-drug’ form of the N- and C-peptide fusion inhibitors that exhibits significant 

microbicidal activity upon use in situ. Our development effort will be based on 

preliminary data obtained with a truncated six-helix bundle that inhibits in vitro infection 

by primary HIV-1 isolates with low nanomolar IC50 values. We propose a 

comprehensive, interdisciplinary approach that combines high-resolution structural 

determination, recombinant protein production and mutagenic analyses, virology, and 

animal model efficacy studies. In this project we seek to conduct in vitro and in vivo 

preclinical and animal model-based research intended to facilitate the development of 

new HIV-1 gp41 peptide fusion inhibitor as a practical microbicide. The Specific Aims 

are: 1. To optimize and identify HIV-1 peptide fusion inhibitors for development as a 

vaginal microbicide. (a) To identify and incorporate specific amino-acid residue 

substitutions that optimize both potency and solubility of fusion inhibitor peptides. (b) To 

develop and optimize robust procedures for the large-scale bacterial expression and 

purification of select fusion inhibitor peptides. (c) Investigate the mechanisms of 
51

resistance to peptide inhibitors so as to avoid eliciting resistance. 2. To characterize the 

specificity, potency and toxicity of optimized peptide fusion inhibitors and their in vitro 

synergistic interactions with the CCR5 inhibitor CMPD167 and the entry inhibitor BMS378806. (a) Determine the virucidal activity of optimized fusion inhibitor peptides 

against a diverse set of primary HIV-1 isolates. (b) Evaluate their toxicity, 

immunogenicity and drug stability in the rabbit model. (c) Study antiviral synergy in vitro 

in order to make rational predictions for lead inhibitor combinations for in vivo efficacy 

testing. 3. To test the effectiveness of the fusion inhibitor peptides to protect against 

mucosal HIV-1 infection. (a) Characterize the specificity and potency of effective peptide 

inhibitors in an in vitro model of HIV-1 infection of human cervical and vaginal tissue. 

(b) Use the NOD/SCID-hu BLT mouse vaginal transmission model to assess the in vivo 

potency and breadth of activity of highly effective peptide inhibitors alone and in 

combination with the small-molecule CCR5 inhibitor CMPD167 and the small-molecule 

entry inhibitor BMS-378806. 

Title: Cervical/Vaginal Mucus and Microbicides

P.I.: Thomas Hope 

Institution: Northwestern University at Chicago 

Grant No.: AI094584-02

Award: $18,750

To develop a functional microbicide it is critical to know how it will interact within HIV 

in the context of the female genital tract. This is a critical issue as previous clinical trials 

have indicated that microbicides do not function as expected in the presence of semen. 

Likewise, other factors, such as cervical/vaginal mucus, might also modulate microbicide 

function. To date, little is known about how HIV interacts with these fluids and how the 

interaction of these fluids changes the local environment. Even less is known about how 

microbicides interact with HIV within this milieu. For example, the vehicle delivering the 

microbicide might interact with the biological fluids of sexual transmission to either 

increase or inhibit HIV acquisition or microbicide potency. The Hope laboratory has 

recently developed methods that allow the transport of HIV with cervical and 

cervical/vaginal mucus to be analyzed and quantified. These studies have revealed that 

mucus can perturb HIV transport and is pH sensitive. At acidic pH, as is found in the 

lactobacilli influenced environment of the vaginal vault, HIV transport is greatly reduced. 

At neutral pH, such as when semen is introduced into the system, HIV transport is 

reduced 10-15 fold relative to what is observed in media (water). Additionally, we have 

found, but not yet published, that virus-binding antibodies can further reduce transport in 

neutral pH cervical mucus. These antibodies do not need to be neutralizing as any 

antibody binding to the virus can decrease virus transport. Semen also contains mucins 

and other components that have the potential to alter HIV transport as we have observed 

in cervical mucus. How HIV is transported within semen and how this changes when 

mixed with mucus or microbicides is not defined. How this process influences HIV 

transport and interaction with mucosal barriers is not understood. In the first phase (R21) 

of this proposal we will define how HIV is transported in semen alone and mixed with 

mucus and/or microbicide vehicles such as carbopol gel and hydroxy ethyl cellulose 
52

(HEC). In the second phase (R33) of this proposal we will extend our studies into the 

environment of the rhesus macaque female genital tract to determine how biological 

fluids and microbicide vehicles alter the way that virus interacts with the mucosal barriers 

of this environment and how these changes can increase or decrease SIV acquisition. 

These studies will lead to a better understanding of how virus interacts with biological 

fluids and how these interactions might alter microbicide efficacy.

Title: Pathophysiologic and Therapeutic Mechanisms of Aspirin 

Exacerbated Respiratory Disorders

P.I.: Joshua A. Boyce 

Institution: Brigham and Women’s Hospital 

Grant No.: AI095219-02

Award: $12,500

This Proposal for support of an Asthma and Allergic Disease Cooperative Research 

Center (AADCRC) grant is focused on the mechanistic basis of aspirin-exacerbated 

respiratory disease (AERD), a distinctive clinical syndrome that accounts for a 

disproportionate percentage of individuals with severe asthma and recurrent nasal polyps. 

AERD is associated with both characteristic clinical reactions to ingestion of nonselective 

inhibitors of cyclooxygenase (COX), persistently elevated generation of the cysteinyl 

leukotrienes (cys-LTs), especially during reactions to aspirin, and selective airway 

hyperresponsivness to leukotriene E4 (LTE4), the most stable and abundant of the cysLTs. We have discovered a molecular pathway through which LTE4 induces pulmonary 

inflammation (requiring P2Y12 receptors and platelets) and vascular leak (requiring a 

putative novel LTE4 receptor, GPR99). We have also discovered that leukocytes from 

individuals with AERD display a defect in expression of COX-2 and COX-2-dependent 

generation of prostaglandin E2 (essential to maintain homeostasis in AERD), and that 

this reverses with desensitization to aspirin. We have also found that platelets and 

leukocytes from individuals with AERD lack the EP2 receptor for PGE2. A team of 

highly accomplished investigators with complementary skills will apply cellular, 

molecular, and whole animal strategies, combined with a proof-of-concept clinical trial to 

determine the cellular and molecular basis for these findings, their relevance to disease 

pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the 

physiologic and functional consequences of EP2 receptor deficiency, and determines its 

epigenetic basis. Project 2 (Y. Kanaoka, PI) will verify the identity and function of 

GPR99 and determine its susceptibility to desensitization and its requirement for 

downstream effectors (platelets, P2Y12, and thromboxane) to elicit physiologic 

responses. Project 3 (E. Israel, PI) will determine the efficacy of P2Y12 antagonism on 

the severity of clinical reactions to aspirin, and the mechanism by which aspirin treatment 

restores COX-2-dependent PGE2 generation. The coordination of the AADCRC is 

enhanced by an administrative Core.

Title: Host and Viral Determinants of Infant and Childhood Allergy and 

Asthma
53

P.I.: Ray Stokes Peebles 

Institution: Vanderbilt University Medical Center 

Grant No.: AI095227-02

Award: $12,500

The long term objective of this application is to define the relationship between infant 

respiratory syncytial virus (RSV) infection and the host response that enables asthma 

inception. There is abundant evidence that children who experience severe RSV 

bronchiolitis during infancy are at greater risk for developing asthma later in childhood; 

however the host and viral determinants of severity of illness are not fully defined. Also 

unknown is whether mild RSV-induced illness in infancy may protect against the 

subsequent development of childhood asthma. In Project 1, we utilize the ReSPIRA 

(Respiratory Study for Protection of Infants from RSV to Asthma) cohort of 2000 infants 

to focus on host immune responses to RSV infection and the subsequent risk of recurrent 

wheezing and childhood asthma. Specifically, in Project 1 we will a) establish the 

relationship between the host phenotypic response to RSV infection in the first 6 months 

of life and the risk of recurrent wheeze and asthma, and b) identify the host genetic and 

immune response determinants of the RSV infection phenotype that affect the 

development of early childhood wheezing and asthma following RSV infection. In 

Project 2, we will focus on the contribution of specific RSV strains to early childhood 

wheezing and asthma development. RSV strains isolated from the ReSPIRA cohort will 

be genotyped and clinical parameters such as bronchiolitis severity score, as well as 

mediators of the host immune response measured in respiratory secretions will be studied 

to determine how RSV genotypes impact the host response. In Project 3, we will utilize a 

mouse model of RSV infection to examine the role of the prostaglandin 12 (PGI2) on 

airway dysfunction of an RSV strain (01/2-20) that has been associated with severe infant 

bronchiolitis and which induces airway pathology in the mouse. We previously reported 

that PG12 and signaling through its receptor (IP) is a critical determinant of severity of 

illness in RSV strain A2 infection. This project will determine the role of host PGI2 in 

RSV airway pathogenesis and also determine if a PGI2 analog currently used in the 

treatment of human disease is a target for RSV bronchiolitis. Further, in Project 3, we 

will use RSV strains isolated from ReSPIRA in Project 2 to determine the 

generalizability of PGI2 as a therapeutic target.

Title: Airway Inflammation and HLA-G in Asthma

P.I.: Steven R. White 

Institution: University of Chicago 

Grant No.: AI095230-02

Award: $12,500

Our program seeks to clarify cellular and molecular mechanisms that lead to chronic 

asthma in order to identify novel, more effective therapies. We concentrate on immune 

mechanisms that underlie chronic airway inflammation with a clear focus on one immune 

tolerance molecule, the class I major histocompatibility complex protein human 

leukocyte antigen (HLA)-G, that we believe has an important role in modulating airway 
54

inflammation that is critical to chronic asthma. The key premise of our AADCRC 

proposal is that understanding the role of HLA-G will lead to new and better therapies to 

alleviate the suffering caused by asthma. To this end we propose three highly integrated 

and related projects: in Project 1, we will examine the presence and regulation of 

expression of HLA-G in asthmatic airways and in the airway epithelium, and relate 

presence to asthma severity and to the expression of regulating microRNA. We will 

examine the regulation of HLA-G expression by key Th2 cytokines such as IL-13 that are 

important to chronic asthma and relate expression back to airway cytokine concentrations 

in chronic asthma. In Project 2, we will exploit naturally occurring genetic variations in 

HLA-G and its LILRB receptors to understand how signaling through HLA-G and its 

receptors regulate the transition of CD4+ lymphocytes to the Th2 phenotype in 

mild/moderate asthma and to the Th17 phenotype in severe asthma. This project also will 

examine how genetic variation in the LILRB receptors modulate the effects of HLA-G on 

both T cell phenotype and on the SHP1 and SHP2 signaling pathways that modulate 

airway smooth muscle hypertrophy in chronic asthma. In Project 3, we will elucidate 

mechanisms that account for the higher risk of asthma among children of asthmatic 

mothers compared to children of non-asthmatic mothers. Using HLA-G as a model of the 

interactions of genotype and asthma status in mother and child, we will identify 

differentially expressed genes and the mechanisms for their differential expression in 

airway epithelium, CD4+ T cells and airway smooth muscle in subjects with chronic 

asthma. To complete these projects, each will interact with a robust Patient Recruitment 

and Data Analysis Core that will recruit 100 carefully phenotyped and genotyped 

asthmatic subjects and additional control subjects, and collect blood and airway 

biological specimens to be used in each project through a Lung Biological Specimens 

Core that will provide analytical and long-term storage. We believe that our current levels 

of productivity and collaboration combined with new, exciting and cutting-edge 

questions in this proposal will allow us to be successful in achieving our overall goal—

identifying novel therapeutic targets for chronic asthma.

Title: T Cell Effector and Regulatory Mechanisms in Asthma and Food 

Allergy

P.I.: Andrew D. Luster 

Institution: Massachusetts General Hospital 

Grant No.: AI095261-02

Award: $12,500

The Massachusetts General Hospital/Harvard Medical School AADCRC entitled T cell 

effector and regulatory mechanisms in asthma and food allergy seeks to gain a better 

understanding of the role of allergen-specific effector and regulatory T cells in 

determining the physiological response to an allergen at mucosal surfaces. It is becoming 

increasingly clear that the net outcome of an inflammatory response is the balance of 

allergen-specific effector T cell activity and opposing regulatory T cell activity. Antigenspecific effector and regulatory T cell numbers and activity are in large measure 

determined by the outcome of allergen-loaded dendritic cell (DC) interactions with 

antigen-specific T cells. The MGH/Harvard AADCRC will explore the balance of 
55

effector and regulatory activity in asthma and food allergy and the ability of tolerogenic 

DCs to affect this balance. The Center will focus on two allergic conditions relevant to 

the mission of the NIAID, namely allergic asthma and food allergy, and utilize two 

clinical models [endobronchial segmental allergen challenge (SAC) and oral 

immunotherapy (OIT)] as a foundation for its studies. Project 1 focuses on the role of 

antigen-specific effector and regulatory T cells in determining airways inflammation and 

airways hyper-reactivity by correlating the numbers, phenotype and function of these 

cells in allergic asthmatics (AA) and allergic nonasthmatics (ANA) using innovative 

imaging techniques; Project 2 focuses on correlating the numbers, phenotype and 

function of these same T cell subsets with clinical outcomes of milk allergic patients 

undergoing milk OIT; and Project 3 focuses on the ability of tolerogenic DC therapy to 

manipulate the balance between these two opposing T cell populations in favor of 

regulatory T cells and tolerance in both asthma and food allergy. The three interrelated 

projects will be supported by Cores that will recruit, enroll and characterize allergic 

subjects for SAC and OIT, provide MHC class II tetramers to specifically identify and 

study allergen-specific T cells, and perform sophisticated transcriptome phenotypic 

analysis on T cell and DC subsets. The goal of this Center is to understand the balance of 

effector and regulatory allergen-specific T cell activity that determines clinical disease in 

asthma and food allergy and to establish the utility of using tolerogenic DCs to 

manipulate this balance to induce allergen-specific tolerance. This would pave the way 

for new therapeutic approaches to treat these and other allergic diseases.

National Institute of Arthritis and Musculoskeletal and Skin 

Diseases 

Title: Role of B Cells and DCs in Lupus Pathogenesis

P.I.: Mark J. Shlomchik 

Institution: Yale University 

Grant No.: AR044077-15A1

Award: $200,000

Breaking T cell tolerance is arguably a critical step in the pathogenesis of SLE. Activated 

T cells provide help to autoantibody-secreting B cells and also infiltrate target organs. 

Therefore it is important to identify how, where and when such T cells are activated and 

how this is maintained. In fact, the latter is critical because any therapy will have to 

interrupt ongoing disease. Lupus-prone mice lacking B cells from birth have markedly 

reduced disease and much less T cell activation. This suggested that B cells are upstream 

in T cell activation and also that they would be good therapeutic targets. However, in 

lupus mice B cell depletion was difficult to achieve using standard anti-CD20 mAb and 

effects, particularly on T cell activation, were not striking. Similarly anti-CD20 failed to 

show clinical effect in SLE patients, though anti-BLyS did. These findings raise the 

question of what the role of B cells really was in ongoing disease, and whether, if 

efficient depletion were possible, would T cell activation and disease be reduced. They 

also suggested that other cell types such as DCs could be as or more important both for 

initiation and propagation. In this proposal we will use genetic approaches to target key 
56

cells and molecules-including deletion during disease rather than from birth-in order to 

unravel the complex interplays of disease mechanisms in vivo. To this end, we recently 

deleted cDC and pDC in lupus-prone MRL.Faslpr mice from birth. Surprisingly, we 

found little effect on T cell activation in secondary lymphoid tissue (SLT), but there were 

striking reductions in nephritis and skin disease, decreased proteinuria and longer 

survival. These data suggested that DCs might be required to activate T cells in target 

tissues-a novel role rather than to initiate activation, as might have been assumed. We 

propose a new model in DCs have non-redundant roles in tissue infiltration in lupus but 

that B cells are the most upstream APC in SLT. To address this model, we will first 

deplete both B cells and DCs during ongoing disease, rather than from birth. This will 

validate DCs as therapeutic targets and help resolve the controversial role of B cells. We 

will also distinguish the roles of cDCs from pDCs, as whether pDCs are important for 

SLE has not been tested experimentally. Second, to understand how B cells and DCs 

might be activating T cells, we will block APC function by deleting MHCII from each. 

Further, we will investigate the role of ICOS signals, which are linked to lupus in a 

number of ways, including emerging data that ICOS specifies T follicular helper (TFH) 

and T extrafollicular helper differentiation, cells that help autoreactive B cells. We also 

have exciting preliminary data that ICOSL on DCs specifically is required to promote 

infiltrating T cells in kidney, and that such cells express Bcl6 and thus may be related to 

TFH. To further investigate the roles of ICOS signals, we will specifically delete ICOSL 

on B cells and on DCs. Together these experiments-organized around Aim 1 focusing on 

B cells and Aim 2 focusing on DCs-will test our model; determine if B cells/DCs or both 

are important as APC; validate B cells, cDCs, and pDCs as therapeutic targets; and 

elucidate the role of ICOS signals in the development of pathogenic T cells.

Title: Osteoarthritis Initiative

P.I.: Michael Nevitt

Institutions: University of California, San Francisco (coordinating center); 

Ohio State University; University of Pittsburgh; University of 

Maryland; Memorial Hospital of Rhode Island

Grant No.: AR022258, 26820120031C*1

Award: $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 
57

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.

Title: Predictors of Pregnancy Outcome in SLE and APS

P.I.: Jane E. Salmon 

Institution: Hospital for Special Surgery 

Grant No.: AR049772-10

Award: $200,000

Pregnancy complications in women with the antiphospholipid syndrome (APS) and/or 

SLE include recurrent miscarriage, preeclampsia, placental insufficiency, and intrauterine 

growth restriction (IUGR). The mechanisms leading to placental and fetal injury in vivo 

are incompletely understood and treatment remains sub-optimal. We have identified 

complement as an early effector in pregnancy loss and/or IUGR associated with placental 

inflammation in a mouse model of APS and shown that complement activation causes the 

release of anti-angiogenic factors and abnormal placental development. The PROMISSE 

Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody 

Syndrome and Systemic lupus Erythematosus) is a first-time effort to translate our novel 

findings in mice to humans and determine if elevations of complement split products 

predict pregnancy complications in patients with antiphospholipid (aPL) antibodies 

and/or SLE. In the first 4 years of this prospective, observational study of pregnant 

patients grouped and analyzed according to the presence or absence of aPL antibodies 

and preexisting SLE, we have enrolled 342 pregnant patients in 7 centers, obtained 

detailed medical and obstetrical information monthly, and serially collected plasma, 

serum, DNA, RNA, and urine. Preliminary data suggest that elevated levels of 

complement activation products antecede and predict poor fetal outcome, consistent with 

our hypothesis that complement is a proximal mediator of fetal loss and IUGR. We 

propose to increase our target sample size from 400 to 700 pregnant patients to maintain 

study power given lower than expected outcome rates, and to leverage the infrastructure 

and rich collection of patient data and samples by expanding the array of biomarkers and 

scope of adverse pregnancy outcomes. Specifically, in Aim 1 we will determine whether 

elevations of split products generated by activation of complement pathways predict poor 

fetal and/or maternal outcome in patients with aPL antibodies and/or SLE and, in Aim 2, 

whether the balance of circulating angiogenic and antiangiogenic factors predicts 

preeclampsia or delivery of IUGR infants. In Aim 3, a new direction, we will use the 

PROMISSE cohort to affirm in humans our recent findings in mice, that certain antiDNA antibodies cross-react with N-methyl D- aspartate receptors (NMDAR) and cause 

neuronal death with ensuing cognitive and behavioral impairment. We propose to 

quantitate anti-NMDAR antibody levels throughout pregnancy in PROMISSE SLE 

patients and test the hypothesis that in utero exposure to maternal anti-NMDAR 
58

antibodies alters behavior and cognitive development in offspring by evaluating cortical 

function tasks in 12 month and 3.5 year old children. This competitive renewal and 

extension of the PROMISSE Study provides an outstanding opportunity to translate 

knowledge from mouse models to patients, define pathogenic mechanisms, identify 

predictors of poor pregnancy outcome in APL and/or SLE, and define novel therapeutic 

targets to prevent such outcomes.Patients with systemic lupus erythematosus (SLE) 

and/or antiphospholipid (aPL) antibodies are at increased risk for miscarriage, 

preeclampsia and fetal growth restriction—major causes of maternal, fetal, and neonatal 

morbidity and mortality in the US and worldwide—whose etiology and mechanism 

remain unknown and for which therapy is limited. In addition to causing placental 

dysfunction, maternal autoantibodies may also directly impair fetal brain development.

Identification of biomarkers that predict poor pregnancy outcome in these patients will 

elucidate mechanisms of disease, define targets for treating patients, and generate 

clinically applicable indicators to permit initiation of interventional trials in patients at 

greatest risk for pregnancy complications.

Title: Sex-Specific Movement Differences in Young Adults with and 

Without Hip Pain

P.I.: Cara L. Lewis 

Institution: Boston University 

Grant No.: AR061690-01A1

Award: $184,162

Acetabular labral tears are an increasingly recognized source of hip pain in young adults, 

especially females, and have been linked to the premature development of hip 

osteoarthritis (OA). Recently, femoroacetabular impingement (FAI) has been implicated 

as a cause of labral injury and OA. In FAI, hip pain occurs in the presence of a structural 

abnormality of the acetabulum or femur which results in early contact between the bones 

during hip flexion and internal rotation. Current treatment for FAI includes surgical 

procedures to resect or reorient the femur or acetabulum or both. While structure does 

contribute to hip pain, increasing evidence suggests that movement patterns may also 

play an important role. The long-term goal of this line of research is to improve treatment 

for hip pain, especially in young adults, which will prevent or slow the progression of 

chondral damage and thereby reduce the need for hip arthroplasty. The purpose of this 

project is to assess the movement patterns of people with FAI compared to people 

without hip pain and to test for sex- and limb-specific differences in these patterns. 

Identification of differences in movement patterns which may contribute to hip pain can 

improve non-invasive treatment for people with hip pain. To test for these differences, we 

will assess movement patterns using kinematic data collected during movements 

including walking, stepping down, supine straight leg raise and prone hip extension on 

subjects with FAI and subjects without hip pain. We hypothesize that subjects with FAI 

will display movement patterns which are closer to their end-range hip motion than 

subjects without hip pain. We believe that these movement patterns contribute to a 

subject’s hip pain. We also hypothesize that females with FAI will display different 

movement patterns than males with FAI. We anticipate this sex difference in movement 
59

patterns because there is an unequal distribution of the structural abnormalities among 

females and males, and because a sex effect has been noted in other lower extremity 

injuries (e.g. ACL tears, patellofemoral pain). Furthermore, as subjects often have 

unilateral pain despite bilateral structural abnormalities, we hypothesize that subjects 

with FAI will display different movement patterns of the painful hip than the unimpaired 

hip. The knowledge gained from this research has the potential to redirect treatment for 

people with FAI by identifying sex-specific movement patterns which could be targeted 

by inexpensive and non-invasive therapeutic interventions. It also could be used to 

develop prevention programs focused on neuromuscular retraining.

Title: NIH Osteoporosis and Related Bone Diseases-National Resource 

Center

P.I.: NIAMS (coordinating center)

Institutions: NIAMS, in cooperation with NIA, NICHD, NIDCR, NIDDK, ORWH, 

and HHS/OWH

Grant No.: 268200800001C*42

Award: $50,000

The National Institutes of Health (NIH) Osteoporosis and Related Bone Diseases ~ 

National Resource Center, a part of the U.S. Department of Health and Human Services, 

provides patients, health professionals, and the public with an important link to resources 

and information on metabolic bone diseases, including osteoporosis, Paget’s disease of 

the bone, and osteogenesis imperfecta. The NIH National Resource Center is dedicated to 

increasing the awareness, knowledge, and understanding of physicians, health 

professionals, patients, underserved and at-risk populations (such as Hispanic and Asian 

women, adolescents, and men), and the general public about the prevention, early 

detection, and treatment of osteoporosis and related bone diseases.

National Institute of Biomedical Imaging and Bioengineering 

Title: Steroid-Based Contrast Agents for Magnetic Resonance Imaging 

of Endocrine Disease

P.I.: Thomas J. Meade 

Institution: Northwestern University at Chicago

Grant No.: EB014806-01

Award: $250,000

The objective of this research proposal is to develop a series of steroid-based magnetic 

resonance imaging (MRI) contrast agents to facilitate molecular characterization of the 

status and function of steroid receptors in hormone-dependent disease and development. 

The ability to detect the location of cell receptors and their concentration throughout a 

living organism is of vital importance as it allows for further understanding of cell 

signaling mechanics. Progesterone and estrogen are steroid hormones that bind to their 

receptors and function as a transcription factors in the nucleus. A non-invasive means of 
60

determining the hormone receptor status of hormone-dependent tumors and benign 

lesions could assist with treatment options, identification of the size and exact location of 

the tumor, and provide additional tools when traditional imaging strategies miss or 

confuse lesions of the breast and uterus. Unlike fluorescence and optical microscopy, 

MRI is not limited by depth or transparency of the specimen. MRI does not use ionizing 

radiation or radioactivity like positron emission tomography (PET) and X-ray/CT, and it 

allows for 3D reconstructions and high resolution imaging over time without the need to 

sacrifice the organism. It is the hypothesis of this grant proposal that gadolinium(III)

conjugated hormone-based contrast agents can target and accumulate in hormone 

receptor positive cells to non-invasively image receptor status. Our preliminary studies 

have identified gadolinium (Gd)-conjugated progesterone derivatives as compounds 

capable of traversing the cell membrane, binding to progesterone receptors, initiating 

gene transcription, and enhancing contrast in mammalian tissues and tumors imaged in 

vivo using magnetic resonance, the most promising of which is termed “ProGlo”. This 

proposal focuses on the application and expansion of ProGlo to enhance the imaging of 

steroid receptor tumors and tissues in vivo. AIM 1. To synthesize and test a series of CAs 

that targets the estrogen receptor. Estrogen-based contrast agents will be designed and 

synthesized with varying polarities, charges, and water solubilities that will selectively 

probe membrane bound receptors or receptors located inside the cells and tumors. AIM 2. 

To investigate if hormone receptor disease of the breast and uterus can be classified as 

receptor positive using functional hormone MR agents. AIM 3. To chemically modify 

CAs to enhance in vivo relaxivity and reduce toxicity by developing and testing bioorthogonal, water-soluble, and multi-chelated hormone CAs. Steroid receptors have 

emerged as attractive targets for molecular imaging due to their role in promoting the 

growth of breast and uterine lesions. This proposal will develop steroid contrast agents 

that could provide a molecular profile of hormone receptor status in cells, validate 

responsiveness to therapy, and improve diagnoses. Functional contrast agents will 

provide valuable tools for use in humans and for immediate use in animal models of 

hormone receptor dependent development and disease without the need to euthanize the 

animal thereby increasing knowledge about developmental biology, disease etiology, and 

progression. 

Eunice Kennedy Shriver National Institute of Child Health and 

Human Development

Title: A Collaborative Workshop Across the Scientific Disciplines 

P.I.: Sally T. Hillsman 

Institution: American Sociological Association, Inc. 

Grant No.: HD010988-01

Award: $10,000

It is well-recognized in the scientific community that data-driven, scientifically rigorous 

tools are needed to stimulate and enhance efforts to use the talents of all our citizens, 

including underrepresented minorities and women. There is an additional need to look 

beyond individual efforts to begin to pursue a system-based analysis. This workshop 
61

proposes to address the recommendation from a 2008 National Institutes of Health 

(NIH)-supported (additional funding provided by the National Science Foundation 

(NSF)) leadership retreat, “Enhancing Diversity in Science: A Leadership Retreat on the 

Role of Professional Associations and Scientific Societies,” regarding the need to 

establish a common standard for measuring and evaluating success of diversityenhancing programs. The workshop further addresses the need to establish a more 

comprehensive and cohesive effort needed to track the many and various efforts of 

government (federal, state, and local), foundations, universities, scientific societies, and 

professional associations. Systematic data collection would allow possible answers to 

broad and important questions such as: To what extent research training should be 

supported collaboratively? What are the best practices that could be adapted that would 

allow for a maximum increase on the return on investment? 

Title: Perioperative Pelvic Floor Rehab: A Randomized Trial

P.I.: Holly E. Richter 

Institution: University of Alabama at Birmingham 

Grant No.: HD041261-12

Award: $25,000

The University of Alabama at Birmingham (UAB) is seeking to successfully compete in 

the third cycle of the NICHD sponsored Pelvic Floor Disorders Network. As a part of this 

important research infrastructure we have demonstrated our credible, productive, 

multidisciplinary clinical approach to the evaluation and treatment of women with pelvic 

floor disorders including urinary and fecal incontinence as well as pelvic organ prolapse. 

We have substantially contributed to the Network activities by participating at all levels 

of clinical trial design, implementation, recruitment, intervention implementation, 

retention and scientific reporting. We have reported outcomes and implication for care of 

these research initiatives at national and international scientific meetings and we are 

committed to continuing these activities. Through this application with its concept 

proposal, we wish to highlight our ability and commitment to continue these meaningful 

research activities. Current common treatment options for fecal incontinence (Fl) include 

behavioral therapy consisting of pelvic muscle exercises, diet and defecatory strategies 

and surgical approaches including anal sphincter repair, artificial bowel sphincter and as 

a last resort, colostomy. A significant proportion of women with Fl, however, do not gain 

benefit from behavioral therapy or sphincter repair yet do not wish to undergo colostomy. 

As the population of post-reproductive women continues to increase, it is imperative to 

study other treatment options that improve quality of life for this condition. An existing 

modality called sacral neuromodulation (SNM, Interstim®) has been FDA approved and 

utilized for the treatment of refractory urge incontinence. Two small randomized trials 

and several cohort studies have shown efficacy of sacral neuromodulation for the 

treatment of refractory Fl (although it is not yet FDA approved for this indication). We 

propose a randomized trial to credibly characterize the effect of SNM on Fl episodes, 

symptom specific quality of life, effect on other pelvic floor symptoms, sexual function, 

predictors of response, adverse events, cost effectiveness and the role of biomarkers in 

optimal and suboptimal responses to this treatment. This information will allow us to 
62

more effectively individualize treatment for women with this condition. RELEVANCE: 

In order to improve on the care and individualized treatment for women with pelvic floor 

disorders, it is important that a credible research program exists that helps guide provider 

care. The Pelvic Floor Disorders Network (NICHD) performs such research and we are 

competing to continue to participate in this important initiative. As a part of this 

application, we propose a concept describing a randomized trial of sacral 

neuromodulation for the treatment of women with fecal incontinence refractory to current 

standard of care treatments. This exciting new treatment modality may help a cohort of 

women with diminished quality of life. 

Title: Pelvic Floor Disorders Network—Duke University Clinical Site

P.I.: Anthony G. Visco 

Institution: Duke University 

Grant No.: HD041267-13

Award: $25,000

Pelvic floor disorders research at Duke University Medical Center (DUMC) is 

sophisticated and comprehensive with committed investigators addressing issues of great 

importance to women. DUMC has a tradition of excellence in clinical care, training and 

research in pelvic floor disorders and includes one of the nation’s first accredited 

fellowship programs in the field. DUMC offers detailed evaluation and treatment in a 

high-volume, multidisciplinary setting that serves as a tertiary referral center for women 

across the southeast US. Each of the five Duke urogynecology investigators is 

fellowship-trained with expertise in both surgical and non-surgical management of 

urinary incontinence (Ul), pelvic organ prolapse (POP), fecal incontinence, and 

defecatory dysfunction. Last year, our Division cared for more than 1550 new patients 

and performed more than 400 surgical procedures for Ul and 270 for POP. Our patient 

population is 80% Caucasian, 15% African American, 2% Asian and 2% Hispanic, from 

both suburban and rural communities with stable care and follow-up patterns. DUMC is 

the hub of a multidisciplinary team of outstanding collaborative investigators in 

urogynecology, urology, colorectal surgery, gastroenterology, maternal-fetal medicine, 

physical therapy and epidemiology. DUMC offers a wide range of diagnostic resources: 

multi-channel urodynamic testing, video urodynamics, cystoscopy, defecography, pelvic 

MRI, endoanal ultrasound, and needle electromyography. During the current PFDN 

cycle, DUMC-initiated three active RCTs: 1. Anticholinergic vs Botox RCT (ABC, Dr. 

Visco, currently enrolling), Interstim vs Botox RCT (ROSETTA, Dr. Amundsen, full 

protocol), and a RCT evaluating transvaginal mesh for prolapse repair (Dr. Weidner, 

mini-protocol planned for fall of 2010. DUMC has consistently been a high recruitment 

site across a wide range of non-surgical and surgical studies with unparalleled retention 

rates. We have proven our ability to support and successfully complete large-scale, multicentered investigations through our robust clinical practice and exceptional research 

infrastructure. Accordingly, Duke University Medical Center is well equipped and 

uniquely qualified to continue as a valuable and productive member of the Pelvic Floor 

Disorders Network. RELEVANCE: Female pelvic floor disorders represent a major 

public health burden given their high prevalence, impairment of quality of life, and 
63

substantial economic costs. As part of the Pelvic Floor Disorders Network, Duke 

University Medical Center is committed to actively participating in innovative clinical 

trials aimed at improving the evaluation and treatment of pelvic floor disorders through 

high-quality, high-impact clinical research. 

Title: Pelvic Floor Disorders Network

P.I.: Charles William Nager 

Institution: University of California at San Diego 

Grant No.: HD054214-07

Award: $25,000

The objectives and aims of this application are for the San Diego site to continue its work 

In the Pelvic Floor Disorders Network (PFDN). The unique strength of our application is 

our proven two site model, which combines the strengths of 7 academic investigators at 

both a tertiary medical center and a large volume HMO. We would like to provide 

leadership, continuity, innovation, academic expertise, a captured diverse patient 

population, and a proven research infrastructure to the network. We have a track-record 

of being the top 2 recruitment in surgical trials for pelvic floor disorders and we want to 

continue that into the third cycle of the PFDN. As noted in the RFA, “In many cases, 

clinicians caring for women with pelvic floor disorders have adopted principles of care 

and surgical techniques before rigorous, objective, controlled evaluation has taken place. 

New devices and techniques have had a dramatic influence on surgical practice...”. Our 

study addresses this concern. Vaginal mesh is probably the most controversial topic in 

pelvic floor disorders and a strong argument can be made that the PFDN is the best group 

to study it. A growing-trend of women is seeking uterine sparing surgery for prolapse and 

a growing trend of gynecologists and urologists are managing uterine prolapse with 

vaginal mesh kit procedures. Our proposed randomized trial of uterine sparing, grafted 

vaginal apical suspension vs. traditional hysterectomy with native tissue suspension 

addresses the very important question of whether it is necessary to remove the uterus to 

treat uterine prolapse. This proposed study recognizes the role of new devices and 

techniques that are changing our care of women with pelvic floor disorders. Our 

comprehensive outcome measures should allow us to answer whether these new uterinesparing, apical vaginal procedures are reasonable alternatives to conventional vaginal 

hysterectomy and native tissue suspension. RELEVANCE: Our site’s participation in the 

next cycle of the PFDN should allow successful network recruitment for surgical trials. 

Uterine prolapse is a very common pelvic floor disorder and we should determine the 

best vaginal surgical treatment for this condition. This proposed research study will 

answer whether uterine-sparing procedures are reasonable alternatives to hysterectomy 

for this condition. 

Title: Cleveland Clinic Clinical Site

P.I.: Matthew Barber 

Institution: Cleveland Clinic Lerner College of Medicine 

Grant No.: HD054215-07
64

Award: $25,000

The goal of the Pelvic Floor Disorders Network (PFDN) is to identify optimum diagnosis 

and management strategies for women with pelvic floor disorders (PFD) using the 

highest quality research methods available. The Cleveland Clinic offers a stable academic 

and research-oriented environment for the conduct of PFDN studies including 

experienced investigators with complementary clinical and research backgrounds that 

have a particular interest and a successful history of conducting clinical trials evaluating 

both surgical and nonsurgical therapies for women with PFD. The specific aims of this 

application are: 1) to demonstrate that the Cleveland Clinic (CC) Clinical Site has 

contributed substantially to the academic, administrative, and clinical aspects of the 

PFDN since joining in its 2nd 5-year cycle; that it possesses the personnel, patient, 

clinical and administrative resources needed for successful participation; and that 

continued participation would be advantageous to the successful attainment of the 

Network’s scientific goals and 2) to present a concept proposal for potential conduct by 

the PFDN. We propose evaluating the comparative effectiveness of sacrospinous 

hysteropexy (SSH), the most well-studied uterine-sparing pelvic organ prolapse (POP) 

surgery, relative to total vaginal hysterectomy with sacrospinous ligament fixation 

(TVH/SSLF), a commonly used hysterectomy-based vaginal uterovaginal prolapse 

procedure. The specific aims of the concept proposal are: 1) compare the anatomic, 

functional, sexual and health-related quality of life outcomes of SSH to TVH/SSLF in 

women undergoing surgery for Stage 2-4 POP uterovaginal prolapse 2 years after 

surgery; 2) compare surgical recovery and short- and long-term morbidity of SSH and 

TVH/SSLF in these same women and 3) determine the incremental cost-effectiveness of 

SSH compared to TVH/SSLF for the treatment of Stage 2-4 POP. Enrolled subjects will 

be randomized in the operating room on the day of surgery to receive either SSH or 

TVH/SSLF (1:1) using a random permutated block design. Randomization will be 

stratified by surgeon to account for the varying experience and expertise. Subjects and 

study coordinators will be blinded to treatment assignment until completion of the study. 

RELEVANCE: Nearly one quarter of all women report symptoms of at least one PFD, 

including prolapse. POP is the most common indication for hysterectomy in 

postmenopausal women and it is unknown whether the addition of hysterectomy to POP 

surgery is integral to successful surgical outcome. The results of our concept proposal 

could justify or eliminate the need for as many as 70,000 hysterectomies in the US each 

year. 

Title: Uterine Leiomyoma Research Center Program

P.I.: Serdar E. Bulun 

Institution: Northwestern University at Chicago 

Grant No.: HD057877-04

Award: $250,000

Uterine leiomyomata (fibroids) represent the most prevalent benign gynecologic disorder 

in the US. The cellular and molecular mechanisms regulating the development and 

growth of leiomyoma are not well understood. Our multidisciplinary team has designed 3 
65

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. We 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. We 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. We 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. We 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 our 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.

Title: Wireless Remote Abdominal Pressure System: Developing a 

More Comprehensive Understanding of Physical Activity and Its 

Association with Incidence, Progression, and Recurrence of 

Pelvic Floor Disorders

P.I.: Ingrid E. Nygaard 

Institution: University of Utah 

Grant No.: HD061787-04

Award: $66,667

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, we concluded that a tool to 

understand how physical activities impact abdominal pressure in the real world does not 

exist. Over the past 18 months, our 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 
66

measures pressure in the upper vagina, an easily accessible space that records pressures 

similar to the true intraabdominal pressure. In this proposal, we plan first to further 

develop an integrated system (the “WRAPS”, Wireless Remote Abdominal Pressure 

System) to monitor intraabdominal pressure outside of the clinical setting. This system 

will consist of three key elements: an intravaginal pressure sensor with wireless data 

transmission capability, a small portable data monitoring and storage unit, and computer 

based data translation software for downloading and managing the pressure data. In a 

controlled exercise laboratory setting, we 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, we will 

characterize intraabdominal pressures experienced by women of varying degrees of 

habitual physical activity and, using WRAPS data as the gold standard, determine 

whether activity can be appropriately categorized in terms of pelvic loading by means of 

self-administered questionnaires, the current standard. Obtaining future evidence about 

the impact of physical stressors on pelvic floor disorders relies on our 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. 

Title: Comprehensive Evaluation of Prolapse Meshes by an 

Interdisciplinary Research Team

P.I.: Pamela A. Moalli 

Institution: Magee-Womens Research Institute and Foundation 

Grant No.: HD061811-04

Award: $66,666

Comprehensive Evaluation of Prolapse Meshes by an Interdisciplinary Research Team 

Each year roughly 200,000 U.S. women undergo a surgery to repair pelvic organ prolapse 

(6, 7). 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, we 

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, we determine how biochemical and structural changes in 
67

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, we 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 our hypothesis, we 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, we will implant meshes transvaginally to characterize the 

distinct host response to this surgical approach. In the third phase, we explore the 

development of future grafts for prolapse surgery. We 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. We 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 associated with certain materials. Indeed, the 

development of such a group is imperative for protecting the health of women. 

Title: Identification of Genes Predisposing to Pelvic Floor Disorders 

P.I.: Lisa Cannon Albright 

Institution: University of Utah 

Grant No.: HD061821-04

Award: $66,667

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. We will perform genome-wide association analysis, using software we 

have developed which allows inclusion of both independent and related cases. We will 

identify all genetic relationships between the sampled POP cases and perform linkage 

analysis in informative, high-risk POP pedigrees. We will identify chromosomal regions 
68

shared Identical by Descent (IBD) in very distantly related cases in these pedigrees, and 

we 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, we will create a population-based resource of 

surgically treated POP cases, we will pursue established and new methods to identify and 

localize predisposition genes affecting POP, and we will begin a detailed search for the 

chromosome 9 gene we have localized.

Title: Genetic Determinants of Uterine Fibroids in African-American 

and Caucasian Women

P.I.: Brahim Aissani 

Institution: University of Alabama at Birmingham 

Grant No.: HD064398-03

Award: $83,333

Uterine leiomyomas (ULs) are the most common pelvic tumors in women of reproductive 

age, accounting for over 600,000 hysterectomies annually in the United States. Several 

lines of evidence support a genetic liability in the pathogenesis of ULs, yet no 

susceptibility gene is known. Advances in research on the genetics of ULs (fibroids) have 

so far been limited by the paucity of genetic epidemiologic studies and infrastructure to 

conduct them. The goal of this epidemiologic study is to evaluate the contribution of a 

region of Chr.1q43 that predisposes to uterine fibroids but remains inadequately 

investigated. Genetic predisposition to ULs has been studied primarily in the context of 

two rare inherited autosomal-dominant conditions, the hereditary leiomyomatosis and 

renal cell cancer (HLRCC) and the multiple cutaneous and uterine leiomyomatosis 

(MCUL1) syndromes, where germline mutations were found in the gene on Chr. 1q43 

encoding the tricaboxylic acid cycle (Krebs cycle) fumarate hydratase (FH) enzyme. 

However, a direct role of this important metabolic housekeeping gene in tumorigenesis 

remains to be proven. Inactivating FH mutations have rarely (< 1-2% of the tumors 

analyzed) been observed in nonsyndromic (common) ULs; however, loss of FH appears 

to be a significant event in the pathogenesis of a subset of these tumors. Furthermore, 

several observations support the existence of an alternative or additional candidate gene 

on Chr.1q43 acting alone or interacting with FH to increase the risk of ULs in susceptible 

individuals: 1) the absence of FH genotype-phenotype correlations, 2) the marked genetic 

heterogeneity in ULs, and 3) the failure to observe ULs or multiple leiomyomatosis in 

siblings or parents of cases with fumarase deficiency, a severe recessive disorder. Taken 

together, these observations underscore the importance of exploring an extended FH 

region in a population-based study of ULs. To this end, we 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. Our study is not intended to shift any 

paradigm about the origins of ULs; rather it will extensively investigate the role of FH in 
69

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. 

Title: Xenograft Study on Growth Control of Human Uterine 

Leiomyomata

P.I.: Takeshi Kurita 

Institution: Northwestern University at Chicago 

Grant No.: HD064402-03

Award: $83,333

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, we 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. Our study clearly demonstrates the 

pivotal role of progesterone in growth and maintenance of UL. The results of our 

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, we will elucidate 
70

the cellular and molecular mechanisms of human UL tumor growth controlled by 172-

estradiol and progesterone. 

Title: Achieving a Critical Mass of Women Biomedical Faculty: Impact 

of Three U.S. Programs

P.I.: Deborah Lynne Helitzer 

Institution: University of New Mexico 

Grant No.: HD064655-04

Award: $175,144

Although there are numerous career development programs for women faculty, women 

continue to leave academic medicine at alarmingly high rates. This study will examine 

the impact on retention and career success of individual women faculty who participated 

in three long-standing national programs, each of which targeted a separate career stage, 

as compared to women and men, at the same career stages, who did not participate in 

these programs. This research also aims to elucidate the patterns and processes that 

contribute to the experience of individuals and their institutions as a means to identify the 

barriers and facilitators—historic and new, individual and institutional—that face women 

faculty in attaining positions of leadership at academic health centers (AHCs) and 

transforming institutional culture. Informed by the guidance of an Advisory Board 

composed of highly respected female and male senior leaders in academic medicine, the 

goal of the research is to assess the impact of participation in intensive career 

development training programs on individual women faculty at early and mid-career 

stages and their institutions, in terms of retention and promotion, while verifying and 

illuminating the ways in which participation in these programs affect career trajectories. 

We will attempt to discover how the findings on retention, academic promotion and 

administrative advancement are influenced by (i) individual dynamics and 

personal/professional development factors addressed in leadership development 

programs; (ii) organizational factors in institutions that send their women faculty to such 

programs; (iii) how these factors may have led to enhancement of leadership 

development and gender experience for women participating in these programs; and (iv) 

how the interaction of these factors has or can lead to a change in organizational culture 

to ensure the ability of institutions to capitalize on the intellectual capital of women 

science faculty members. Along with this retrospective analysis, we will prospectively 

identify new emerging challenges that affect women Assistant and Associate Professors 

attending intensive career development programs, and create an infrastructure for future 

research on retention and promotion. Additionally, this study will provide a 

comprehensive set of findings which can serve as the basis for a future design of an 

innovative women-focused leadership program as well as providing helpful information 

on the culture change needed to improve recruitment and retention of America’s leading 

scientific minds. 

Title: A Controlled Trial of Gabapentin in Vulvodynia: Biological 

Correlates of Response
71

P.I.: Candace S. Brown 

Institution: University of Tennessee Health Science Center 

Grant No.: HD065740-02

Award: $200,000

Approximately 14 million U.S. women have provoked vestibulodynia (PVD), a type of 

localized vulvar pain which causes major disruption in the everyday lives of up to 60% of 

affected women and negatively impacts sexual function in 45%. The financial burden 

imposed on the health care system is also significant, as these women visit multiple 

clinicians and specialists, and try numerous, unproven treatments. To date, few 

randomized controlled trials (RCTs) have been conducted to establish evidence based 

protocols for PVD management. The first immediate goal is to conduct a multicenter 

RCT of gabapentin treatment for PVD. Gabapentin was selected because of its efficacy in 

treating other neuropathic pain conditions and the promising, preliminary data on its use 

in PVD. This is a significant research project because PVD is a highly prevalent, chronic 

pain condition that is costly to the health care system and that currently has limited 

management options available to affected women. The second immediate goal is to 

define psychophysiologic measures of gabapentin response and to define 

mechanistically-based PVD subtypes, which may be related to abnormalities in central 

sensitization, muscle hypertonicity, and autonomic dysregulation. Identifying predictors 

of treatment response in PVD would have clinical applicability to other chronic pain 

syndromes, and is consistent with NIH’s mission to investigate coexisting pain conditions 

in order to identify common etiological pathways and develop therapeutic targets. The 

specific aims are (1): to test the prediction that pain from tampon insertion (primary 

outcome measure) is lower in PVD patients when treated with gabapentin compared to 

when treated with placebo. Additional outcome measures include reported intercourse 

pain and 24-hour pain, and (2) to test the prediction that gabapentin treatment will reduce 

mechanical allodynia, reduce area and duration of hypersensitivity induced by 

intradermal capsaicin, reduce vaginal muscle pain to palpation, decrease the number and 

intensity of somatic tender points, and increase cardiac beat-to-beat variability. This 16-

week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 

women between 18-50 years of age who report tenderness localized to the vulvar 

vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. 

Electronically entered daily diaries will be used to determine if pain is lower in PVD 

subjects when treated with gabapentin (up to 3600 mg/d) compared to when treated with 

placebo. The approach is innovative because it focuses on an understudied condition, in a 

multicenter setting, using a novel outcome measure (the tampon test), and a newly 

developed web-based recruitment and patient-reporting tool. Data management will 

include a mechanism-based analysis of drug effectiveness. These study outcomes will 

ultimately lead to our long-range goal of identifying underlying pathophysiologic 

mechanisms of PVD in order to create evidence-based differential diagnoses of subtypes 

of PVD for more effective and cost-effective management options. 

Title: Pittsburgh Pelvic Floor Research Program

P.I.: Halina M. Zyczynski 
72

Institution: Magee-Womens Research Institute and Foundation 

Grant No.: HD069006-02

Award: $25,000

The purpose of this proposal is to demonstrate the capabilities of the University of 

Pittsburgh to participate as a clinical site in the NICHD-sponsored Pelvic Floor Disorders 

Network (PFDN). Our site has a longstanding track record of successful contribution to 

multicenter studies of urinary and fecal incontinence, and pelvic organ prolapse. We are 

particularly well suited to be a clinical site in the PFDN because of our volume, research 

infrastructure and track record, basic and translational experience and expertise. Access 

to large numbers of nulliparous women enables us to contribute uniquely to studies of the 

role of pregnancy and parturition in the etiology and prevention of pelvic floor disorders 

(PFDs). Magee-Womens Hospital (MWH) is the central resource for gynecologic 

specialty care for the 19 hospital University of Pittsburgh Health System serving a very 

large aging population. Our site brings expertise in urogynecology, physical therapy, 

geriatrics, urology, gastroenterology and mental health. We offer unique technical 

expertise in genomics, proteomics, tissue regenerative techniques, biochemical and 

biomechanical impact of meshes on the vagina and central neuronal control of bladder 

function. We propose to establish a comprehensive, scientifically rigorous clinical and 

translational research program within the PFDN for prospective comparative studies of 

mesh materials used in prolapse and incontinence procedures. The program will generate 

data of immediate clinical relevance as it will present scientifically sound, vendor 

independent evidence to guide surgeons’ selection of specific graft materials and 

evidence-based practice guidelines for management of mesh complications. The 3 major 

components of the proposal are: 1) mesh specific infrastructure for implementation in 

PFDN clinical trials employing mesh inclusive of the development of a Mesh Morbidity 

Index and establishment of a Biospecimen Repository 2) the first RCT of meshes selected 

through rigorous analyses of biomechanical and biochemical properties and 3) 

translational studies on the cellular response to mesh materials and pathophysiology of 

mesh complications. The RCT will serve to pilot the database, compare clinical outcomes 

of meshes whilst providing specimens for translational studies. 

Title: Pelvic Floor Disorders Network Clinical Sites

P.I.: Lily A. Arya 

Institution: University of Pennsylvania 

Grant No.: HD069010-02

Award: $25,000

The goal of this application is to competitively identify clinical sites to conduct clinical 

trials for female pelvic floor disorders. This application from the University of 

Pennsylvania with Lily Arya MD, MS (Epidemiology) as Principal Investigator 

demonstrates our research plan for a new treatment for urge urinary incontinence, 

myofascial physical therapy. This potentially effective and safe method will greatly 

enhance treatment choice and improve the quality of life of women with urge urinary 

incontinence. This application outlines our extensive experience with similar large multi-
73

center clinical trials. We highlight our ability to recruit and maintain subjects in female 

pelvic floor disorder clinical trials, noting we have been one of the leading recruitment 

centers in the nation for similar trials. We have often been able to recruit a greater 

number of subjects than our original estimates. The facilities at the University of 

Pennsylvania are supportive and outstanding. Our existing research unit and personnel 

has continuously demonstrated highly successful management of large clinical trials with 

outstanding organization, attention to detail and compliance with Good Clinical Practice, 

federal regulations and local Institutional Review Boards. Dr. Arya is an active researcher 

in the field of health measurement for pelvic floor disorders and she has successfully 

conducted a number of clinical trials in women’s health. Specifically, she and her team of 

co-investigators and staff have been actively involved in surgical and non-surgical trials 

for urinary incontinence. She will bring significant expertise regarding study design and 

health measurement research to the Pelvic Floor Disorders Network. She leads a team of 

co-investigators who have a track record of collaborative clinical and translational 

research. We feel that the combination of a high quality personnel, experience in the 

research area, ability to recruit, and outstanding management and organization will 

contribute to a high likelihood of successful completion of this and future trials of 

treatment methods of pelvic floor disorders. RELEVANCE: The University of 

Pennsylvania has the expertise, infrastructure and experience to be a significant 

contributor to the Pelvic Floor Disorders Network. The proposed study, to investigate the 

efficacy of a new treatment for urge urinary incontinance, will improve quality of life of 

women with urge incontinence and result in considerable savings of health care 

resources. 

Title: Brown/WIH Pelvic Floor Disorders Network Site

P.I.: Deborah Lee Myers 

Institution: Women and Infants Hospital of Rhode Island 

Grant No.: HD069013-02

Award: $25,000

The mission of the PFDN is to identify optimal diagnosis and management strategies for 

women with pelvic floor disorders (PFDs) and this is directly in line with Women and 

Infants Hospital (WIH)/Brown’s mission and commitment. WIH is a women’s hospital, 

focused solely on advancing women’s health and research and our extremely high 

volume, stable patient base, expertise of our multi-disciplinary collaborative and 

established research infrastructure provide the ideal environment to conduct large-scale, 

clinical research at the highest level. The aim of this application is for WIH/Brown to 

become the first PFDN site in New England by demonstrating: 1)our academic 

productivity and experience in multi-site, collaborative surgical, pharmaceutical and nonsurgical clinical trials; 2)highly committed investigators with expertise in research 

methods and a specialized research team qualified to conduct multiple protocols, manage 

high quality data, and maintain high recruitment and retention; 3)a long-standing, formal 

relationship with multi-disciplinary collaborators committed to advancing the care of 

women with PFDs led by Urogynecology (including Urology, Colorectal surgery, 

Women’s Gastroenterology, Women’s Physical Therapy, and Women’s Radiology); and 
74

4)our high clinical volume (In 2009, the Division of Urogynecology evaluated 1211 new 

patients and performed 583 PFD surgical procedures; vaginal, abdominal, laparoscopic 

and robotic approaches are all represented). We present a concept proposal describing a 

3-stage, randomized trial of a combined non-surgical and surgical approach to treatment 

of mixed urinary incontinence (MUl) in women who have failed conservative therapy 

and/or elect surgical treatment. Women suffering from MUl are at high risk for failure of 

segregated treatments and are often excluded from clinical trials focused on either stress 

or urge urinary incontinence alone. Clinical management of MUl remains a challenge and 

trials targeting this population are urgently needed. WIH has a long-standing history of 

supporting network collaboratives and our goal is to participate and become a leader in 

the PFDN in terms of protocol development and completion, data interpretation and 

quality, recruitment and retention and high quality dissemination of findings. 

RELEVANCE: Female pelvic floor disorders including urinary incontinence, pelvic 

organ prolapse and fecal incontinence are common, disabling conditions and are a 

significant public health issue. Although a variety of treatment options exist, high quality 

evidence to guide clinical management and to improve treatment specificity is still 

needed. Through the PFDN, WIH/Brown is committed to advancing high quality 

scientific evidence to help improve the care of women and reduce the burden of these 

disorders. 

Title: RCT of Hypnotherapy vs. Tpolterodine for OAB: Voiding and 

Brain Activation Changes

P.I.: Rebecca Glenn Rogers 

Institution: University of New Mexico Health Sciences Center 

Grant No.: HD069025-02

Award: $25,000

The University of New Mexico (UNM) proposes to join the Pelvic Floor Disorders 

Network (PFDN) to achieve the Network’s primary goal of conducting rigorous, multicenter clinical trials to investigate the clinical and health aspects of pelvic floor disorders 

in women. Our site, in collaboration with other Network sites, aims to reduce the burden 

of pelvic floor disorders on women and their families. Through the design of innovative 

trials and participation in ongoing studies, the UNM PFDN site will make significant 

contributions to the Network. Dr. Rogers, Principal Investigator, and Dr. Komesu, 

Alternate Principal Investigator, have extensive experience in the design and conduct of 

multi-center randomized trials and proven leadership and productivity. The UNM PFDN

site brings to the Network a busy clinical service with large numbers of underrepresented Hispanic and Native American populations, as well as broad institutional 

support from the Department of Obstetrics and Gynecology and a recently funded 

Clinical and Translational Research Center. The concept proposal, based on preliminary 

data generated by our site and the work of others, is an innovative investigation 

comparing hypnotherapy to long-acting anticholinergic medicine for the treatment of 

overactive bladder (OAB). In addition to the hypnotherapy comparative-effectiveness 

trial, the concept proposal focuses investigation into the underlying mechanisms of OAB 

on the brain, using functional magnetic resonance imaging (fMRI). This translational, 
75

comparative effectiveness clinical trial is an excellent example of cutting edge research 

that the UNM PFDN site will bring to the Network. Skilled investigators, a busy clinical 

practice, unique patient populations and broad institutional support make UNM a worthy 

new clinical site for the PFDN. RELEVANCE: Pelvic floor disorders are common and 

costly. Performance of rigorously designed, target randomized clinical trials that inform 

evidence-base health care practices for women with pelvic floor disorders is best done 

through collaboration with other clinical sites. The University of New Mexico is a highly 

productive clinical and research site and proposes to join the Pelvic Floor Disorders 

Network in order to meet the Network’s goal of investigating innovative solutions to 

these common problems. 

Title: Unintended Birth, Fetal, and Infant Loss and Maternal Depressive 

Symptoms

P.I.: Pamela J. Surkan 

Institution: Johns Hopkins University 

Grant No.: HD069731-01A1

Award: $81,000

Depression is the most prevalent mental health disorder and globally is two times more 

likely to occur in women. In rural areas of Bangladesh, women’s autonomy in planning 

pregnancy and the likelihood of successful pregnancy remain uncertain, with stillbirth, 

perinatal and neonatal death occurring at over five-fold higher rates than in developed 

countries. These rates are likely to be higher for rural women with little access to medical 

care. Our aims are to study: 1) the relation of unintended pregnancy to maternal 

depressive symptoms in the third trimester of pregnancy and at six months postpartum; 2) 

the relation of unintended pregnancy and fetal and neonatal loss to postpartum maternal 

depressive symptoms; 3a) whether the relation of unintended pregnancy with postpartum 

maternal depressive symptoms differs by gender of the offspring; and 3b) whether the 

relation of fetal or neonatal loss with postpartum maternal depressive symptoms differs 

by gender of the offspring. Miscarriage, stillbirth, perinatal death, and neonatal death will 

be examined separately as risk factors. The proposed secondary analysis uses data from a 

population-based, randomized antenatal micronutrient supplementation trial conducted 

from 2001 to 2007 in northwestern rural Bangladesh among ~60,000 pregnant women. 

Women were enrolled in early gestation and followed through 6 months postpartum. 

Pregnancy outcomes and infant vital status were monitored weekly through 3 months of 

age. In the third trimester and at 6 months, symptoms of depression were elicited by 

maternal responses to questions about common depressive symptoms as well as about 

suicide. Statistical methods will include descriptive analyses and calculation of adjusted 

risk ratios to examine unintended pregnancy and fetal and neonatal death events as 

predictors of subsequent depressive symptoms. We will assess the effects of pregnancy 

intent from each parent as well as discordance between maternal and paternal pregnancy 

intentions on maternal depressive symptoms. Documentation of unintended pregnancy 

and loss of a fetus or infant as risk factors for depressive symptoms in a large South 

Asian population will help to show their extent and guide interventions relevant to a 
76

vulnerable period when maternal mental health is critical for the healthy development of 

her other children. 

Title: Consortium to Evaluate a Novel Violence Prevention Program on 

College Campuses

P.I.: Corrine M. Williams 

Institution: University of Kentucky 

Grant No.: HD069897-01A1

Award: $180,193

Up to 25% of women may be sexually assaulted during college, and one-third of college 

students have experienced physical aggression from dating partners. While most students 

neither participate in nor condone violence, many respond passively to a campus culture 

that may tacitly support violence, as evidenced by violent media images, jokes 

trivializing violence against women, and sexual harassment. Growing awareness that all 

members of the campus community can play a significant role in ending dating and 

sexual violence (DV/SV) has led to an increase in violence prevention interventions for 

college students. However, very few of these programs have been empirically evaluated. 

A significant barrier to progress in intervention research is the infrastructure required to

implement and evaluate interventions across multiple sites. For this project, the 

intervention will be Green Dot, an innovative primary prevention intervention to reduce 

DV/SV among college students, which was developed at the University of Kentucky. The 

intervention consists of one-hour persuasive speeches, followed by a six to either hour 

bystander intervention training called Students Educating and Empowering to Develop 

Safety (SEEDS). In addition, we are creating booster sessions that will be provided to all 

students who have completed SEEDS training to assist with additional skills-building that 

may be required. As a developmental project, the proposed research will consist of three 

phases: 1) pilot work to create survey modules, resulting in a questionnaire that contains 

measures which are standardized across campuses to evaluate the effectiveness of the 

intervention and is a manageable length; 2) data collection at UK to streamline data 

collection procedures when other colleges are brought on; and 3) recruitment of 

additional implementation and control college sites. The University of Kentucky will 

operate as the coordinating center for the multi-site evaluation and will continue to serve 

as the pilot site or data collection and refinement of study methodology. The University 

of South Carolina has agreed to serve as an implementation site and the University of 

Cincinnati has agreed to serve as a control site. We will recruit an additional eight 

colleges (four control and four intervention sites) during the project period. By beginning 

with this R21 to conduct developmental work and begin problem solving, we can help to 

ensure the success of subsequent projects. If Green Dot is then determined to be effective 

across multiple campuses in preventing violence and the associated sequelae of adverse 

academic, as well as physical and mental health outcomes, experienced by so many 

college students, then the potential impact of this study is indeed groundbreaking. 

Additionally, the lessons learned from establishing a multi-site public health intervention 

trial, with one coordinating center responsible for all data collection via online surveys, 

has implications for the study of other health issues. 
77

Title: Mothers and Others: Family-Based Obesity Prevention for Infants 

and Toddlers

P.I.: Margaret E. Bentley 

Institution: University of North Carolina at Chapel Hill 

Grant No.: HD073237-01

Award: $100,000

Despite increases in obesity among infants and toddlers, few published interventions 

promoting healthy diet and decreased sedentary behaviors among this age group exist. To 

fill this gap, we propose a randomized controlled trial among 468 Non-Hispanic black 

women, their families, and their child caregivers to test the efficacy of a multicomponent, tailored intervention versus an attention control (child safety) in promoting 

healthy weight gain patterns during infancy. The proposed intervention, Mothers and 

Others: Family-based Obesity Prevention for Infants and Toddlers will be one of the first 

to meet the unique needs of individual families by delivering anticipatory guidance on 

infant care, feeding and growth through multiple channels and to multiple caregivers. 

Primary modes of delivery for the intervention arm will include face-to-face counseling 

through 9 home visits (1 by a certified Lactation Consultant), 6 tailored health newsletters 

for mothers and 6 targeted health newsletters for “other” caregivers deemed influential by 

mothers, as well as ~160 cue-based text messages for mothers and “other” caregivers. 

The control group will receive messages on child safety delivered through general 

newsletters and text messages. Our main outcome is infant/toddler growth, captured by 

mean weight-for-length z-scores (WLZ) at 18 months, mean change in WLZ between 0-

18 months, and likelihood of overweight (WLZ e 95th percentile) at 18 months. 

Differences between groups are expected to be achieved through uptake of targeted 

health behaviors, including a greater likelihood of breastfeeding initiation, exclusivity 

and duration; after 6 months, higher dietary intakes of whole fruits and vegetables and 

lower intakes of energy-dense snack foods; longer durations of infant and toddler sleep 

and fewer night awakenings; and, lower levels of television and electronic media 

exposure. We further hypothesize that these targeted health behaviors will be achieved 

through modifiable risk factors underpinning the intervention, namely more positive 

breastfeeding attitudes; higher levels of parenting and breastfeeding self-efficacy; higher 

levels of perceived social support; higher responsive feeding style scores; improved 

accuracy in perceiving infant/toddler weight status; and, diminished parental perceptions 

of infant fussiness. We believe Mothers and Others is highly significant and innovative, 

as it targets a minority population at high risk of early life obesity, it begins during 

pregnancy, a “teachable moment” for establishing healthy behaviors, it actively engages 

multiple child caregivers, and it utilizes novel intervention platforms, including tailoring 

and text messaging. We have assembled a strong, interdisciplinary team of researchers, 

each with an outstanding record for implementing and publishing research relevant to this 

intervention. Collectively, we have experience conducting similar interventions in this 

population; designing, implementing and evaluating the proposed tailoring and novel 

technology components; recruiting and retaining a similar cohort; and measuring and 
78

analyzing relationships between the proposed modifiable risk factors, targeted health 

behaviors and outcomes of early life growth. 

Title: A Pharmacokinetic Evaluation of Levonorgestrel Implant and 

Antiretroviral Therapy

P.I.: Kimberly K. Scarsi 

Institution: Northwestern University at Chicago 

Grant No.: HD074462-01

Award: $150,734

Family planning services, including hormone contraceptives, are critical for HIV-infected 

women, in whom prevention of unintended pregnancy not only decreases maternal and 

child mortality, but also reduces the risk of mother-to-child HIV transmission. Similarly, 

antiretroviral therapy (ART) is a lifesaving intervention tha improves the health and 

economic status of HIV-infected women throughout the world. Therefore, it is of 

significant public health importance to guide the appropriate use these essential 

medications. To this end, millions of HIV-infected women in low and middle income 

countries (LMIC) currently use or are gaining access to subdermal progestin-containing 

implants as a preferred method of long-acting reversible contraception. These implants 

are often combined with ART despite the lack of critically needed pharmacokinetic (PK) 

drug-interaction data to inform their safe and effective concomitant use. Highlighting this 

concern are several case reports of unintended pregnancy that occurred in patients with 

subdermal progestin-containing implants concurrently receiving non-nucleoside reverse 

transcriptase inhibitor (NNRTI)-based ART, the most commonly used ART in LMICs. 

While NNRTIs are known to significantly decrease oral pill progestin concentrations, no 

data are available to inform healthcare providers of the impact of NNRTIs on progestin 

concentrations following release from subdermal implants. To fill this critical gap in 

knowledge, the overall aim of this proposal i to conduct a PK study to evaluate the 

combination of a levonorgestrel (LNG) implant and NNRTI (nevirapine or efavirenz)-

based ART in HIV-infected Ugandan women. We hypothesize that lower LNG 

concentrations will be observed in patients on NNRTI-based ART and although the 

implant’s efficacy may be retained initialy, this negative interaction will jeopardize 

implant effectiveness near the end of its intended duration of use (4 years). The specific 

aims of this project are (1) to characterize the PK of LNG released from a subdermal 

implant over one year in HIV-infected women with and without NNRTI-based ART and 

(2) to evaluate the potential for a bidirectional drug-interaction resulting from the longterm impact of chronic progestin exposure on antiretroviral concentrations. To achieve 

these aims, we will enroll 20 HIV-infected women into each of three study groups: a 

control group not receiving ART and two treatment arms consisting of patients receiving 

nevirapine- or efavirenz-based ART. Using sparse PK sampling strategies, LNG, 

nevirapine or efavirenz concentrations will be measured over one-year and compared 

between and within groups, as appropriate. The LNG data will also be used to develop a 

PK model that will predict LNG disposition over the following three years of intended 

use, allowing for identification of the safe duration of LNG implant use in women on 

NNRTI-based ART. At the conclusion of this project, the first evidence-based medical 
79

knowledge will be available to guide the safe and effective concomitant use of subdermal 

LNG implants and NRTIs, thereby improving management of reproductive health in 

millions of HIV-infected women worldwide. 

Title: Effect of Feeding Buddies on Adherence to WHO PMTCT 

Guidelines in South Africa

P.I.: Kiersten Ann Israel-Ballard 

Institution: Program for Appropriate Technology in Health 

Grant No.: HD075090-01

Award: $300,000

The 2010 revised WHO recommendations to provide antiretroviral (ARV) prophylaxis or 

treatment to mothers or infants during the breastfeeding period indicate a paradigm shift 

in PMTCT care and treatment programming. Yet despite South Africa’s adoption of this 

guidance, myriad challenges currently exist. Confusion in the public health care system 

related to mixed messaging around safe infant feeding and the provision of-and now 

withdrawal of-free formula milk have made adherence to exclusive breastfeeding a 

challenge in South Africa. Cultural, social, and psychological factors influence the ability 

of women to follow PMTCT guidelines, which include exclusive breastfeeding for six 

months, adherence to ARV prophylaxis or treatment, and early infant diagnosis. Facilitybased interventions alone are often inadequate to effect sustained behavioral changes in 

the face of multiple contextual factors. Community- and home-based support are needed, 

yet cost and systems constraints make these infeasible in many PMTCT programs. Our 

previous data suggest that a feeding buddy strategy could fill this gap and provide a 

home-based support system for the mother. The feeding buddy, who is selected by an 

HIV-positive pregnant woman to support her in overcoming sociocultural challenges to 

adhering to various aspects of PMTCT programs, is not an employed health care worker, 

but rather an individual known to the mother, making the intervention extremely costeffective, and requiring minimal resources to implement. PATH is proposing a 

comprehensive evaluation of the feeding buddy concept in one health district of South 

Africa. The goal of the proposed study is to evaluate the effect of a feeding buddy to 

support mothers to adhere to PMTCT recommendations in order to establish feasible 

models of promoting HIV-free infant survival in resource-limited settings. We 

hypothesize that mothers who choose a feeding buddy will have increased rates of 

exclusive breastfeeding and adherence to ARV prophylaxis or treatment, as well as 

improved rates of early infant diagnosis and stigma reduction. A prospective cohort 

intervention study, set within a comprehensive ongoing national program addressing 

maternal and child health will be conducted with the following aims: (1) to determine the 

effect of a feeding buddy on adherence to exclusive breastfeeding and (2) to determine 

the effect of a feeding buddy on adherence to ARV prophylaxis or ART regimens. 

Secondary aims are: (1) to determine the effect of a feeding buddy on adherence to infant 

HIV testing at 6 weeks and (2) to determine the effect of a feeding buddy on disclosure 

and stigma. HIV-infected pregnant women (n=600) will be given the opportunity to 

choose a feeding buddy at an antenatal care visit to support infant feeding and PMTCT 

recommendations; follow-up will be to six months postpartum. Feeding buddies could be 
80

a simple, low-cost strategy for strengthening existing facility-level efforts to implement 

the new PMTCT guidelines, and ultimately could contribute toward improving HIV-free 

survival. 

Title: ORWH/NICHD Leiomyoma Tissue Bank

P.I.: James Segars

Institution: NICHD Intramural Research Program

Award: $50,000

Uterine fibroids represent a health disparity and affect an average of one-in-four 

reproductive age women in the U.S. (1). The effect on reproduction is considerable as 

fibroids are estimated to add $34 billion annually to cost of health care in the U.S. In 

response to a need identified by the research community, the ORWH-NICHD Fibroid 

Tissue Bank was established to serve as a repository source of well-characterized fibroid 

and matched control tissues for NIH-funded investigators pursuing basic research on 

fibroid growth and pathogenesis. The overarching objective of this collaborative initiative 

between ORWH and NICHD is to improve understanding of the mechanisms and 

pathophysiology of fibroid disease. The improved understanding of fibroid-related 

cellular change is expected to serve as a foundation for development of new and novel 

treatment approaches. Since the establishment of the tissue bank, we have collected a 

total of 933 tissue specimens; 851 from fibroids and 82 from control-matched myometrial 

tissue. The samples are well characterized and preserved in order to permit RNA, DNA, 

metabolomics, and protein analysis. Patients from minority populations are well 

represented: 36% of patients were African American, 44% were Caucasian, and 19% had 

unknown or unreported race or ethnicity. Of note, the bank reflects the unusual diseases 

unique to the NIH: 57% of patients have rare conditions including HLRCC (14 patients), 

MEN-I, tuberous sclerosis, and Birt-Hogg-Dubé syndrome. This patient group represents 

40% and 50% of the total fibroid and myometrial specimens, respectively, and 41% of 

the total specimens. 

National Institute of Diabetes and Digestive and Kidney Diseases

Title: Diabetes Prevention Program Outcomes Study

P.I.: Sarah E. Fowler 

Institution: George Washington University 

Grant No.: DK048489-19

Award: $1,050,000

The George Washington University Biostatistics Center proposes to continue as the 

Coordinating Center for the Diabetes Prevention Program Outcomes Study (DPPOS). 

This application is companion to the Clinical Centers’ application. The Diabetes 

Prevention Program (DPP), a multi-center controlled clinical trial in a multiracial 

population of overweight persons with impaired glucose tolerance, established the 

efficacy of a life-style intervention aimed at a modest degree of weight loss and increased 
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moderate-intensity activity, and of metformin in decreasing the development of diabetes 

by 58 and 31%, respectively. The DPPOS, a 10-year follow-up, was funded in 2002 for a 

five-year period with the understanding that it would require refunding via competitive 

renewal. The overarching goal of DPPOS was to study whether the relatively shortterm 

benefits of delaying diabetes demonstrated in the DPP would translate into a more longlasting impact that would reduce the public health burden of the diabetes epidemic. 

Specifically, DPPOS had the following major goals: 1) to determine the effects of DPP 

interventions on the long-term microvascular and cardiovascular disease (CVD) 

complications, atherosclerosis and CVD risk factors; 2) to examine the long-term effects 

and durability of prior DPP interventions on further diabetes development; and 3) to 

describe the incidence of long-term complications and their risk factors in new onset type 

2 diabetes and IGT. To date, after 10 years of DPP/DPPOS, 93% of the DPPOS cohort 

attends annual follow-up visits. A durable effect of diabetes prevention associated with 

the life-style and metformin interventions has been demonstrated with 36 and 19% 

reductions in diabetes incidence, respectively, compared with the placebo group. Interim 

analyses also reveal significant reductions in CVD risk factors in the intervention groups, 

with decreased utilization of medications. The development of diabetes is associated with 

an increased frequency of retinopathy and microalbuminuria. The development of 

diabetes is associated with an increased frequency of retinopathy and microalbuminuria. 

This application is designed to support completing the second five-years of DPPOS 

focusing on complications that require more time to develop. RELEVANCE: The 

Diabetes Prevention Program (DPP) and first 5 years of the DPP Outcome Study 

(DPPOS) have demonstrated that a lifestyle intervention program aimed at weight loss, 

and metformin, prevent diabetes development over a 10 year period. Completion of 

DPPOS will examine the impact of diabetes prevention on long-term complications 

affecting the eye, kidney, nerves and heart, and remains critical to public health.

Title: Molecular Basis of E. Coli Adhesins in Bladder Disorders

P.I.: Scott J. Hultgren 

Institution: Washington University 

Grant No.: DK051406-15A1

Award: $200,000

Over 15 million women suffer from urinary tract infections (UTI) annually in the U.S., 

~85% of which are caused by uropathogenic Escherichia coli (UPEC). 20-40% of 

patients suffer from multiple and/or chronic recurrences and increasingly are left with 

few treatment options other than costly long-term antibiotic prophylaxis Indiscriminate 

use of antibiotics is leading to increased resistance to first-line empiric therapie such as 

trimethoprim-sulfamethoxazole and the undesirable use of fluoroquinolones for empiric 

treatment of UTI. Catheter-associated UTI (CAUTI) further exacerbates this problem. 

Consequently, multi-drug resistance is rising rapidly. Thus, there is a critical need for 

new therapeutics to better treat and prevent chronic recurrences. There are two bladder 

associated niches for UPEC during acute UTI: the bladder tissue and the luminal 

space/urine. FimH, the type 1 pilus adhesin mediates UPEC colonization and invasion of 

human and murine bladder epithelial cells (BECs). Murine models indicate that after 
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invasion, UPEC can subvert innate expulsion mechanisms and escape into the cytoplasm 

where rapid bacterial replication results in the formation of intracellular bacterial 

communities (IBC) comprised of 104-105 bacteria. IBCs are transient and upon IBC 

maturation bacteria disperse from the biomass, filament, and spread to neighboring 

BECs, re-initiating the IBC cycle. This cycle potentiates the establishment of infection 

allowing the expansion of the bacterial population in a sequestered habitat protected from 

host immune and antibiotic clearance. Bacterial colonization of BECs, IBC formation, 

filamentation and biofilm formation on urinary catheters (also seen in mouse models) are 

all processes seen in human disease. Further, the fimH gene is under positive selection in 

UPEC clinical isolates consistent with its role in UTI. Murine models and human clinical 

studies show roles for the same specific cytokines and TLR4 signaling in UTI. In 

humans, UTI ranges from asymptomatic bacteriuria to acute self-limiting infection to 

chronic/recurrent UTI. Murine models mimic these disease outcomes and reveal that the 

nature of host response dictates whether a UTI resolves or develops into long-lasting 

chronic/recurrent UTI. This grant proposal will use a panel of virulent clinical isolates 

including a multi-drug resistant strain that has spread globall, to focus on a direct 

experimental investigation of common but complex clinical problems associated with 

more severe UTI and/or recurrence. Aim 1 investigates mechanisms by which 

superinfection of UPEC leads to the development of chronic/recurrent infection. Aim 2 

investigates catheterization, which may alter the pathogenesis and may trigger the 

recurrence of infection in patients with a history of UTI. Aim 3 investigates the efficacy 

of potent small molecular weight compounds called mannosides, which block FimH 

function, to treat and prevent UTI in the context of these complicating factors. The 

proposed experiments will elucidate how sequential infection and catheterization affect 

the course of UTI and aid in better clinical management and the development of new 

therapeutics for combating this prevalent infection.

Title: The Look AHEAD Continuation: Action for Health in Diabetes

P.I.: Rena R. Wing 

Institution: Miriam Hospital 

Grant No.: DK056992-14

Award: $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 
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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 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 cardiovascular-related factors and complications, and cost-effectiveness of the 

intervention.

Title: Urinary Incontinence Treatment Network: DCC

P.I.: Sharon L. Tennstedt 

Institution: New England Research Institutes, Inc. 

Grant No.: DK058229-12

Award: $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 E-BE-DRI) of Phase I. Primary Aims of TOMUS are to compare objective and 

subjective cure rates for stress incontinence at 12 and 24 months between the retropubic 

and transobturator midurethral sling procedures. Performance of these procedures is 

increasing rapidly with limited data available on safety and efficacy. Therefore, this study 

will compare the efficacy and safety of the retropubic and transobturator (inside-out and 

outside-in) procedures in a 2-arm RCT; 588 women with stress Ul will be enrolled. 

Primary Aim of E-SISTEr is to compare long-term (60 mos.) effectiveness and durability 

of the Burch colposuspension and autologous fascial sling for treatment of stress Ul in a 

randomized cohort of 655 women. Primary Aim of E-BE-DRI is to examine long-term 

(26 mos.) durability of the addition of behavioral treatment to drug therapy for treatment 

of urge Ul in a randomized cohort of 307 women. The UITN is a multi-disciplinary, 

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.
84

Title: Ovarian Hormone Suppression and Regulation of Adipogenesis in 

Women

P.I.: Wendy M. Kohrt 

Institution: University of Colorado Denver 

Grant No.: DK092718-02

Award: $191,250

Estradiol (E2) deficiency triggers weight gain, and specifically abdominal fat gain, in 

women. The shift toward central adiposity after menopause likely contributes to 

increased risk for the metabolic syndrome and associated chronic diseases (i.e., type 2 

diabetes, coronary artery disease, hypertension). The long-term aim is to understand the 

mechanisms by which E2 deficiency mediates increases in abdominal adiposity. The 

primary aim (PA1) of the R21 is to determine whether ovarian hormone suppression in 

premenopausal women, which is known to cause fat gain, triggers an increase in 

adipogenesis (i.e., increase in cell number) in abdominal adipose tissue. This will be 

assessed by measuring the changes in cell size distribution and the incorporation of 

deuterium (2H) into DNA of cells in the non-stromal (i.e., mature adipocyte) fraction. 

Secondary aims are to determine: SA2) effects of ovarian hormone suppression on 

mRNA expression of factors involved in adipogenesis (C/EBP1, PPAR3) and markers of 

macrophage infiltration (CD68, Emr-1) and inflammation (IL-6, TNF-1); and SA3) 

whether new adipocytes arise from non-resident bone marrow progenitor (BMP) cells 

using cell surface markers (Notch 4, Platelet-derived Growth Factor Receptor (PDGFR) 

2, Integrin 15, CD36) that enable detection by flow cytometry. To achieve these aims, 24 

premenopausal women will be studied before and after 30 and 60 days of ovarian 

hormone suppression via gonadotropin releasing hormone agonist therapy with add-back 

of placebo (GnRHAG+PL) or estradiol (GnRHAG+E2). Hypotheses are: H1a) 

GnRHAG+PL for 60 days will result in a larger increase in small adipocytes (< 40 5m) 

when compared with GnRHAG+E2. Because fat mass increases during GnRHAG+PL, 

an increase in the number of small adipocytes will be interpreted as an increase in 

adipogenesis and not as evidence of adipocyte atrophy; H1b) The incorporation of 2H in 

the non-stromal cell fraction DNA will be increased in response to GnRHAG+PL, as 

compared with GnRHAG+E2. Because the non-stromal fraction contains mature

adipocytes, an increase in 2H-enriched DNA should reflect adipogenesis; H2) Ovarian 

hormone suppression will increase mRNA expression of factors associated with 

adipogenesis, macrophage infiltration, and inflammation (C/EBP1, PPAR3, CD68, Emr1, IL-6, TNF-1) when compared with baseline (before vs after GnRHAG+PL) and when 

compared with E2 add-back (GnRHAG+PL vs GnRHAG+E2); and H3) Ovarian 

hormone suppression will increase BMP-derived adipocytes when compared with 

baseline (before vs after GnRHAG+PL) and when compared with E2 add-back 

(GnRHAG+PL vs GnRHAG+E2). To the best of our knowledge, this will be the first in 

vivo study of the role of E2 as a regulator of adipogenesis in humans. Because it is 

believed that adipocytes are programmed to achieve a certain volume of fat, an increase 

in adipocyte number would lead to a gain in fat mass that would be very difficult to 
85

reverse. Thus, identifying strategies that effectively prevent an increase in adipogenesis 

during ovarian hormone withdrawal would be of high clinical importance.

Title: Weight Management in Obese Pregnant Underserved AfricanAmerican Women

P.I.: Samuel Klein 

Institution: Washington University 

Grant No.: DK094416-02

Award: $100,000

Maternal obesity and inappropriate gestational weight gain (GWG) increase both 

maternal and neonatal morbidity and mortality. In addition, offspring of obese women are 

at increased risk for neurodevelopment delay, becoming obese, and developing metabolic 

diseases. Women who are socio-economically disadvantaged (SED), especially from 

African American (AA) populations, are particularly susceptible to adverse pregnancyrelated outcomes because of their high prevalence rates of obesity. Therefore, successful 

weight management during pregnancy in SED, AA women has considerable public health 

implications. We have experience in testing lifestyle interventions among SED nonpregnant women that have been implemented and sustained within community 

organizations such as Parents As Teachers (PAT), a national home visiting program that 

provides parent-child education and services free-of-charge to high needs women, 

prenatally and post-partum, through up to 25 home visits per year until kindergarten. We 

propose to conduct a 24-month (6-month prenatal and 18-month post-partum) 

randomized, controlled trial in obese SED AA women to evaluate the ability of an 

innovative lifestyle intervention program (PAT-i-), delivered by PAT parent educators 

during prenatal and post-partum home visits, to improve maternal and neonatal/infant 

weight, metabolic and health outcomes. An extensive programmatic evaluation will 

determine the applicability of the PAT+ intervention in real world settings by measuring 

programmatic reach, implementation, acceptability, and sustainability. If effective, PAT+ 

can be disseminated through this national organization, which currently reaches over 

249,000 mothers and 319,000 children participating in 2,173 PAT programs across all 50 

states.

Title: Lifestyle Interventions in Overweight and Obese Pregnant 

Women

P.I.: Xavier Pi-Sunyer 

Institution: St. Luke’s Roosevelt Institute for Health Sciences

Grant No.: DK094463-02

Award: $100,000

A randomized controlled trial is proposed to study the effect, in a cohort of racially and 

ethnically diverse group of overweight and obese pregnant women, of an Intensive 

Lifestyle Intervention (ILI) compared to Usual Care (UC) on gestational weight gain 

(GWG), infant fatness, and mothers’ post-delivery weight retention. Women in the ILI 
86

arm will receive intensive counseling during pregnancy and group counseling after 

delivery regarding behavior, nutrition, and physical activity change. Visits to counselors 

will be weekly and additional telephone and internet contacts will occur. The mothers’

will be assessed at 14 and 36 weeks of pregnancy and at 12 weeks and 52 weeks postdelivery. The measurements will be anthropometry, whole body MRI, EchoMRI, and 

whole body plethysmography (BodPod). The infants’ measurements will be 

anthropometry, whole body MRI, EchoMRI, and whole body plethysmography (PeaPod) 

for fatness 12 weeks and 52 weeks. Mothers and children will have cardio-metabolic risk 

factors measured in plasma. Data will be collected regarding mothers’ dietary intake and 

physical activity (questionnaires and accelerometry) to assist in counseling. Other data to 

be collected include questionnaires on quality of life, socio-economic status. Careful 

record will be kept of expenses in providing the ILI, so that cost analysis of the 

intervention can be calculated. The study is powered on the primary outcome, fatness of 

the infants at birth. We require 180 participants to attain appropriate power. We will 

enroll 210 so as to allow for some dropouts along the way. Each mother will be followed 

during pregnancy and for a year post delivery. Each infant will be followed for a year 

after birth. We have the ability o continue to follow these participants if further funding is 

forthcoming, as they are all local to or hospital’s catchment area and our own physicians. 

If aims are achieved, namely that both children and mothers profit from the intervention, 

there should be a paradigm shift in how overweight pregnant women are treated. At 

present, there is a dearth of behavioral advice and intervention relating to GWG and 

physical activity provided to these women. Positive results from our study would provide 

evidence for ILI preventative intervention.

Title: Glycated CD59 as a Novel Biomarker of Gestational Diabetes 

Mellitus

P.I.: Jose A. Halperin 

Institution: Brigham and Women’s Hospital 

Grant No.: DK095429-01A1

Award: $200,000

The goal of this proposal is to assess glycated CD59 in human serum as a pathogenically 

relevant early bio-marker for screening of gestational diabetes mellitus (GDM). This 

proposal is highly translational and addresses major Public Health priorities because 1) 

diabetes affects H 25 million Americans, 2) and GDM is a major source of adverse 

pregnancy outcomes including macrosomia and pre-eclampsia. The proposed work opens 

the possibility of using glyCD59 as a biomarker for GDM, an innovative departure from 

the use of OGTT, a cumbersome, costly and time-consuming test with poor 

reproducibility and many times unwanted effects including nausea and vomiting. A 

simpler, easy to use, patient friendly marker that is also involved in the pathogenesis of 

diabetes and its complications may help fulfill an important clinical need in the 

widespread screening for GDM and prevention of associated adverse outcomes. The 

applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided 

evidence for a link between the complement system and the pathogenesis of the 

complications of diabetes, and 3) developed key reagents that allow quantification of 
87

glycated hCD59 in human fluids and tissues. Specifically, we have demonstrated that 1) 

glycated CD59 is present in target organs of diabetic complications, and 2) glyCD59 can 

be readily measured in normal urine and serum. Furthermore, our preliminary data show 

that glyCD59 is a) significantly increased (3-4 fold) in the serum of diabetic and prediabetics individuals, and b) seems to respond faster than HbA1c to changes in glycemic 

load within an individual All necessary tools and expertise to accomplish our aim are 

available in the laboratory of the applicant and expert collaborators, including 

monoclonal antibodies specific for glycated CD59 and assay calibrators, access to large 

and diverse population of pregnant women undergoing pre-natal care at BWH, and 

diagnostic tools, equipment and expertise to necessary to conduct all studies proposed in 

the application. Successful accomplishment of our aims would represent a major 

advancement in screening and early diagnosis of GDM.

Title: Bedside to Bench—Role of Androgen and Estrogen Receptor 

Signaling in Pulmonary Arterial Hypertension

P.I.: Robert Danner

Institution: National Institute of Diabetes and Digestive and Kidney Diseases

Award: $80,000

Idiopathic pulmonary arterial hypertension (IPAH), a subtype of plexogenic pulmonary 

arteriopathy (PAH), is a rare disorder associated with poor survival. Despite consistent 

epidemiological evidence demonstrating a 2 to 4 fold female predominance in IPAH, the 

underlying mechanisms for this imbalance are unclear. Endothelial dysfunction resulting 

from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary 

vascular injury, the so-called two-hit hypothesis, appears to play a central role both in the 

pathogenesis and progression of PAH. Inflammation may drive this dysfunctional 

endothelial phenotype, propagating cycles of injury and repair in genetically susceptible 

patients with IPAH and patients with disease associated PAH (e.g. scleroderma, HIV, and 

sickle cell disease). Histologic specimens from patients with IPAH reveal the presence of 

inflammatory cells, including macrophages and T- and B-lymphocytes, within classic 

plexiform lesions that are the hallmark of PAH. Pulmonary artery endothelial cells 

(PAECs) in PAH orchestrate the recruitment of inflammatory cells as well as secreting 

pro-inflammatory and pro-coagulant cytokines into the circulation. Patients with IPAH 

have higher levels of circulating IL-1β, IL-6, P-selectin and E-selectin in comparison to 

healthy controls. Therefore, targeting PAEC inflammation may interrupt the cycles of 

injury/inflammation and repair that contribute to progressive increases in pulmonary 

vascular resistance in patients with PAH, and thereby delay or prevent right ventricular 

failure and death. Both estrogen and testosterone promote vasodilatation and affect 

vascular inflammation through binding to estrogen (ER) and androgen receptors (AR), 

respectively, members of the nuclear receptor (NR) family of transcription factors. 

However, the interaction between sex hormone signaling and IPAH-associated vascular 

injury/inflammation is not understood. Many NRs inhibit inflammation through a transrepression mechanism that recruits co-repressor proteins to promoter NFκB and AP-1 

binding sites in a tissue and target gene specific manner. Using an in silico bioinformatics 

approach, we found that the androgen receptor (AR) is relatively over-expressed in 
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primary human endothelial cells compared to phagocytic leukocytes. Initial work in our 

laboratory using EA.hy926 cells, a human endothelial line, demonstrates that 

dihydrotestosterone (DHT) can suppress TNFα-induced VCAM1 mRNA expression, 

while spironolactone, a mixed mineralocorticoid receptor and AR antagonist currently 

used in PAH for advanced right heart failure, was found to inhibit NFκB signaling. We 

hypothesize that AR and ER differentially modulate endothelial inflammation in IPAH 

and this may in part explain the female predominance of this disease. Here, the effects of 

AR and ER signaling on endothelial dysfunction and inflammation will be investigated in 

cell culture models. Patients with PAH will be recruited to the NIH to investigate novel 

MRI-based methods to improve clinical phenotyping and as part of a pilot feasibility 

study on the effects of early spironolactone on endothelial inflammation in vivo. The 

Specific Aims include: 1.) Investigate the effects of AR and ER in endothelial cell culture 

systems that simulate key aspects of PAH pathophysiology using proinflammatory 

challenges (IL-1β, IL-6, IFNγ), targeted gene knockdown (eNOS, BMPR2) and dominant 

negative mutant protein expression (Smad proteins); 2.) Characterize the global 

transcriptomic response of naïve and dysfunctional PAECs (BMPR2 and/or eNOS 

silencing; Smad dominant negative mutant expression) to plasma from patients with PAH 

compared to matched controls using oligonucleotide microarrays; and 3.) Patients with 

PAH will be recruited to the NIH for a pilot study of early treatment with spironolactone 

to investigate its effects on endothelial dysfunction in vivo. In addition to standard 

clinical assessment (6-minute walk distance, echocardiography and right heart 

catheterization), plasma levels of inflammatory cytokines, neurohormonal markers and 

novel MRI-based techniques for assessing pulmonary artery endothelial function will be 

used to characterize treatment response. Using 6-minute walk distance as the gold 

standard measurement of functional status, we will determine the sensitivity and 

specificity of MRI-based quantification of pulmonary artery endothelial function and 

MRI derived measurements of right ventricular (RV) structure and function for assessing 

disease progression.

National Institute on Drug Abuse

Title: Novel Assessment of Maternal Distress Tolerance Underlying 

Substance Use Relapse

P.I.: Carl W. Lejuez 

Institution: University of Maryland, College Park 

Grant No.: DA034176-01

Award: $228,000

Women evidence worse substance use treatment outcomes than men (Greenfield et al., 

2007), including higher rates of treatment dropout (Arfken et al., 2001; King & Canada, 

2004; Sayre et al., 2002), lower treatment attendance (McCaul et al., 2001) and higher 

rates of post-treatment substance use relapse (Grella et al., 2006). Yet, substance abuse 

research often includes little attention to gender-specific factors relevant to particular 

vulnerabilities of female participants (Brady & Ashley, 2005; Greenfield et al., 2007). 

One factor especially relevant to risk of relapse for many female drug users is maternal 
89

stress; child care responsibilities and the associated stressors may significantly increase 

risk of substance use relapse, particularly during high-risk periods for relapse following 

substance abuse treatment. Further, although maternal factors have been a particular 

empirical and clinical focus regarding environmental risk factors for drug using women, 

but the large preponderance of this research is focused on the impact of maternal 

substance use on child outcomes, with little attention to drug use outcome for these 

women as an important target in its own right (cf., Pajulo et al., 2006). Accordingly, one 

promising factor that may help explain the maternal distress and substance use 

association when reintroduced to one’s home environment following discharge from 

substance abuse treatment is maternal distress tolerance, or the ability to tolerate distress 

due to parenting issues. Indeed, one’s ability to tolerate distress is associated with relapse 

following substance abuse treatment and length of abstinence attempts. However, despite 

its relevance to both substance use and parenting responses, little is known about the 

impact of low distress tolerance on substance using mothers. This may be due, at least in 

part, to the lack of distress tolerance assessment strategies that target directly the unique 

experience of maternal distress. To address the lack of research in this area, the following 

R21 attempts to provide an initial examination of maternal risk factors for substance use 

relapse, with a focus on the moderating role of distress tolerance. As a secondary aim, we 

explore a novel and ecologically valid measure of maternal distress tolerance to examine 

its utility over a standard distress tolerance task. Specifically, we will include 105 

predominantly low-income, inner-city African American substance using mothers in their 

last week of residential drug use treatment that have a child in the critical age of 9 months 

to 4 years to examine the link between several indices of maternal distress and substance 

use outcomes with both general and maternal-specific measures of ability to tolerate 

distress as moderators of this relationship. 

National Institute of Environmental Health Sciences

Title: Dioxin Exposure and the Invasive Pathogenesis of Endometriosis

P.I.: Kevin G. Osteen 

Institution: Vanderbilt University Medical Center 

Grant No.: ES014942-06

Award: $250,000

Endometriosis, described as the ectopic growth of endometrial tissue, is a debilitating 

disease of reproductive age women. In North America, at least 5.5 million women are 

affected by endometriosis at any one time and estimates of the economic cost of treating 

this disease range from $1-20 billion annually in the United States alone. An emerging 

view is that a reduced endometrial responsiveness to progesterone (P4), a defect referred 

to as the “endometriosis phenotype,” may play a significant role in development and/or 

progression of endometriosis. Relative to this question, we have explored whether 

exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin or dioxin) promotes 

development of the P4- resistant, endometrial phenotype. During our past funding period, 

we utilized adult human endometrial cell and tissue culture models, a chimeric model of 

experimental endometriosis in immunocompromised mice and a murine model of early 
90

life TCDD exposure to examine the impact of this toxicant. Using human cells, TCDD 

exposure was found to disrupt the anti-inflammatory action of P4, leading to cellular 

changes that potentiated the invasive behavior of endometrial tissues in our experimental 

endometriosis model. Our murine model of early life toxicant exposure revealed that 

TCDD-mediated defects in uterine P4 sensitivity can indeed arise from a developmental 

exposure. Perhaps more significant, our murine model also revealed that early life 

toxicant exposure leads to a heightened sensitivity to inflammation for multiple 

generations in the absence of additional toxicant exposure. Taken together our studies 

strongly suggest that disrupting the anti-inflammatory action(s) of P4 during endometrial 

maturation is the key mechanism by which TCDD-like toxicants alter reproductive 

function and impact a woman’s risk of developing endometriosis. Thus, therapeutic 

interventions which target inflammatory signaling may have significant efficacy in 

blocking TCDD-mediated development of the P4 resistant endometrial phenotype 

associated with endometriosis. To validate this appoach we will utilize in vitro and in 

vivo studies designed to prevent the development and progression of the endometriosis 

phenotype as well as prevent the transmission of this phenotype to future generations. We 

propose three Specific Aims: 1): To evaluate the therapeutic potential(s) of resveratrol 

(RES) and PGE2 signaling inhibitors to reduce TCDD mediated loss of P4 

responsiveness in human endometrial cells.. 2): To evaluate whether the antiinflammatory effect(s) of RES and PGE2 signaling inhibitors alone or in combination 

will limit TCDD-mediated growth of experimental endometriosis in our humanized 

Rag2?(c) mouse model. 3): To evaluate the ability of RES and PGE2 signaling inhibitors 

to restore uterine progesterone sensitivity and reproductive function in a novel murine 

model of early life TCDD exposure that exhibits an adult endometriosis-like uterine 

phenotype.

Title: Ex Vivo Female Reproductive Tract Integration in a 3D 

Microphysiologic System

P.I.: Teresa K. Woodruff 

Institution: Northwestern University at Chicago 

Grant No.: ES022920-01

Award: $300,000

The female reproductive tract is responsible for producing endocrine hormones, 

developing mature, healthy gametes (oocytes) and providing the site for fertilization and 

an environment that supports fetal development. There are five main organs in the female 

reproductive tract-the ovary, fallopian tubes, uterus, cervix and vagina. Each organ is 

responsible for unique aspects of reproductive function, but act integrally to support 

overall endocrine health, fertility, and fetal development. The reproductive tract organs 

are assembled from multiple cell lineages to create individual follicles (that enclose and 

support oocytes), oviductal/fallopian tubes, uterine myometrium and endometrium, the 

cervix and the vagina. Traditionally, research of the female reproductive tract has relied 

on two-dimensional (2D) cultures of isolated primary cells or immortalized cell lines 

grown on plastic and independent of adjacent cells, tissue architecture, and functional 

context. Moving to a three-dimensional (3D) culture environment has allowed us to better 
91

understand the function and interaction of cells within individual organs and interrogate 

interactions between tract tissues in co-cultures (e.g., the follicle and the ovarian surface 

cells, or the uterine myometrium and endometrium) to measure responses to normal 

reproductive hormones, pathologic conditions (such as high levels of androgens) or 

exposure to endocrine disruptors. New biomaterials and 3D culture systems have now 

presented us with the exciting opportunity to create a complete in vitro reproductive tract 

whereby each of the cultured organs can be assembled into a linked perfusion culture 

system. Just as the biological function and responses of 2D monolayer cell cultures differ 

from those of 3D-cultured organoids, we predict that the biology of the reproductive 

organs when studied in an integrated series will more closely recapitulate the in vivo 

environment. In Aims 1 and 2, we propose to develop in vitro cultures of human 

reproductive tissues that phenocopy in vivo function in terms of hormone production and 

response to the physiologically relevant reproductive hormones follicle-stimulating 

hormone (FSH) and estrogen. We will use the 3DKUBE culture platform (KIYATEC), 

which not only permits control of perfusion to mimic tissue circulation, automated 

sampling for pharmacokinetic analyses, tissue imaging and in situ bioassays, but also will 

facilitate integration of the individal organ cultures into a functional in vitro female 

reproductive tract culture system in Aim 3. The successful development of an ex vivo 

female reproductive tract will give us the unique ability to interrogate normal hormonal 

responses of each organ in the context of the complete reproductive tract, as well as 

examine responses of the organs and system to agents that pose reproductive hazards. 

Toxicologic testing on female reproductive function and fertility is currently limited to 

animal studies. Our proposed Ex Vivo Female Reproductive Tract Integration In a 3D 

Microphysiologic System would permit earlier assessment of the effects of drugs, 

toxicants or vaccines on the human female reproductive system prior to exposure in 

clinical trials.

National Institute of General Medical Sciences 

Title: Pharmacogenetics of Phase II Drug Metabolizing Enzymes

P.I.: Richard M. Weinshilboum 

Institution: Mayo Clinic

Grant No.: GM061388-13

Award: $237,958

This proposal represents a request for continued funding of the Mayo Clinic 

Pharmacogenomics Research Network (PGRN) grant “Pharmacogenetics of Phase II 

Drug Metabolizing Enzymes”. 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. We 
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have used that approach to study the pharmacogenomics of the 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, we have performed pharmacogenomic genome-wide association 

(GWA) studies of breast cancer, and we will soon perform similar studies of the SSRI 

therapy of depression. We 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. We 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. RELEVANCE: 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 PGRN will apply modern pharmacogenomic 

techniques to help make it possible to “individualize” the drug therapy of breast cancer 

and depression.

National Institute of General Medical Sciences & Indian Health 

Service

Title: Oklahoma Native American Research Centers for Health (NARCH 

VI)

P.I.: Gloria Ann Grim 

Institution: Cherokee Nation

Grant No.: GM092238-02

Award: $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 
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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.

Title: Research To Improve Preconception Health of Adolescent 

Women (NARCH VI)

P.I.: Sara Jumping Eagle 

Institution: Oglala Lakota Oyate

Grant No.: GM087165-03

Award: $128,436

The Oglala Sioux Tribe, in partnership with Stanford Research/University of South 

Dakota School of Medicine and the Oglala Lakota College, will be addressing priority 

health issues identified by the tribe and to support and expand the research capacity and

infrastructure that will build on the research foundation that has been developed within 

the tribe over the past decade. Particular attention will be given to undertaking research to 

improve the preconception health of adolescent girls. 

National Institute of Mental Health

Title: Adjunct Aripiprazole for Symptomatic Hyperprolactinemia in 

Female Schizophrenia

P.I.: Deanna L. Kelly 

Institution: University of Maryland, Baltimore 

Grant No.: MH090071-02

Award: $189,455

Risperidone is available generically and one of the most widely used antipsychotic 

medications; but is associated with elevated prolactin. This elevation is particularly 

pronounced in women and most recent studies show that the vast majority of women 

have elevated prolactin levels with approximately 50% also having the corresponding 

side effects of amenorrhea, oligomenorrhea or galactorrhea. Elevated prolactin may be 

associated with sexual dysfunction, decreased quality of life, medication nonadherence 

and decreases in bone mineral density over time. Lowering the dose or switching 

medications due to this side effect in stabilized patients is not a practical option in most 

cases. There is little evidence to guide treatment in this important area however dopamine 

agonists such as bromocriptine or amantadine may exacerbate symptoms, have lacking 
94

efficacy data and are associated with side effects. We have sizeable pilot data to suggest 

that a low dose of aripiprazole (10 mg/day), a dopamine partial agonist, added to 

Risperidone can improve symptomatic prolactin side effects. We will complete a double 

blind randomized 16-week control trial examining adjunct aripiprazole (10 mg/day with 

increase to 15 mg/day at 8 weeks if no response) vs. placebo in 70 women with 

symptomatic hyperprolactinemia and hypothesize it will be effective in the resolution of 

amenorrhea, oligomenorrhea and galactorrhea. We also hypothesize that aripiprazole will 

significantly improve quality of life, personal well-being and sexual function. And, we 

will examine improvements in positive, negative and depressive symptoms, sex hormone 

levels and measures of bone turnover. The significance and innovation of this application 

is high as this is a significant complaint and concern of women and very little evidence is 

available to guide treatment in women who are stabilized and doing well on antipsychotic 

treatments but develop these significant side effects. If funded, this important treatment 

research study of adjunct aripiprazole treatment will provide invaluable data and 

treatment options for thousands of women who suffer from schizophrenia and will help 

move the field towards better tailoring and personalizing antipsychotic treatment, 

particularly for women who suffer from these problems. 

Title: Treatment of PTSD in Residents of Battered Women’s Shelters

P.I.: Dawn M. Johnson 

Institution: University of Akron 

Grant No.: MH095767-01A1

Award: $300,000

Intimate partner violence (IPV) is a pervasive social problem associated with high rates 

of posttraumatic stress disorder (PTSD). Moreover, PTSD is associated with considerable 

morbidity and a higher risk of re-abuse in victims of IPV. Domestic Violence Shelters 

provide an integral resource for IPV victims in that they provide emergency shelter, 

support, and access to community resources that can aid in their establishing long-term 

safety for themselves and their children. However, PTSD symptoms can compromise 

battered women’s ability to access and effectively use these vital personal and social 

resources, effectively establishing safety for themselves and their children. Despite the 

fact that annually 300,000 battered women and children access shelter services, and 

domestic violence shelters provide a prime time to initiate psychological treatment, 

virtually no research has systematically investigated the treatment of PTSD in residents 

of battered women’s shelters. To address this gap in the literature, we have developed a 

shelter-based treatment for victims of IPV with PTSD, Helping to Overcome PTSD 

through Empowerment (HOPE). HOPE is a brief cognitive-behavioral treatment that that 

adopts an empowerment approach to treatment, emphasizing stabilization and safety, 

goals consistent with the theoretical and empirical literature on battere women and PTSD. 

HOPE is a novel treatment in that it adopts an empowerment approach to treating PTSD 

and emphasizes stabilization and safety; important needs of residents of battered 

women’s shelters with PTSD. In this application we propose to expand upon our pilot 

work with HOPE and test the efficacy of HOPE relative to supportive therapy (i.e., 

Present Centered Therapy, PCT) in a sample of 186 female residents of battered women 
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shelters with IPV-related PTSD. In an effort to facilitate future dissemination of HOPE, 

sessions will be delivered by community therapists and the study will be conducted in a 

range of shelter systems. Furthermore, the current proposal, unlike our pilot work, will 

compare HOPE to an attention matched control condition, have a longer follow-up period 

in order to determine whether positive findings are sustained over time, will assess the 

impact of HOPE on child abuse potential, will incorporate objective measures of stress 

responding (e.g., attentional biases and physiological reactivity to trauma cues), will 

explore novel mediators and moderators of treatment, and will include a costeffectiveness analysis. Findings will be used to inform a future dissemination study of 

HOPE. 

Title: Course and Predictors of Depressive Relapse During IVF

P.I.: Lee S. Cohen 

Institution: Massachusetts General Hospital 

Grant No.: MH096006-01A1

Award: $248,607

This revised proposal is an R21 application for the ORWH Funding Opportunity 

Announcement “Advancing Novel Science in Women’s Health Research (ANSWHR)” 

(PAS-10-226). Major depressive disorder (MDD) is prevalent in women of reproductive 

age, and the course of MDD across infertility treatment and implications for clinical 

management have not previously received systematic study. At this time, clinicians do 

not have evidence-based treatment guidelines on which to rely in order to advise women 

with histories of MDD who plan in vitro fertilization (IVF) or other assisted reproductive 

procedures. The context of infertility treatment is an intriguing and clinically compelling 

setting for the stuy of the biological stress response, hypothalamic-pituitary-adrenal 

(HPA) axis dysregulation, and risk for major depression. The aims of the study are: 1) to 

delineate the clinical predictors of depressive relapse in women with histories of 

depression across a period of six months while they are undergoing IVF including: 

antidepressant continuation or discontinuation, previous course of depressive illness, 

duration of attempt to conceive, and partner support, 2) to describe the trajectory of 

depressive symptoms over the course of IVF cycles, and 3) to explore biological markers 

of the stress response, including those pertaining to HPA axis dysregulation and 

inflammation associated with depressive relapse and stress during IVF treatment. We will 

conduct a prospective naturalistic investigation in which participants (N=60) will each be 

followed longitudinally for six months, during which time they will proceed through at 

least one IVF cycle. Mood symptoms, antidepressant use, psychotherapy, perceived 

stress, partner support, use of gonadotropins and any hormonal interventions, and all 

infertility based treatments and interventions across each cycle will be tracked 

prospectively. The significance of the proposal is derived from: 1) its public health 

implications in light of the high prevalence rats of both infertility and major depression in 

women, 2) the lack of systematic data regarding risk of depressive relapse and predictors 

of relapse in women undergoing IVF, and 3) the need for systematic study of the 

biological sequelae of stress among women with histories of depression undergoing 

treatment for infertility. 
96

Title: Trajectories of Reward Sensitivity and Depression Across 

Adolescence

P.I.: Greg Hajcak 

Institution: Stony Brook University, The State University of New York

Grant No.: MH097767-01

Award: $200,000

There is increasing focus on changes in reward sensitivity that take place across 

adolescence; in particular, puberty appears to be a time characterized by increased 

sensitivity to rewards. At the same time, puberty is a time characterized by a significant 

increase in depressive symptoms, and depression is characterized by reductions in 

sensitivity to rewards. The current project examines reward sensitivity as a latent trait, 

capitalizing on a combination of EEG, functional neuroimaging (fMRI), behavioral, and 

self-report measures. Along the same lines, we consider multiple assessments of 

depressive symptoms (e.g., parent and child reports) so that depressive symptoms can 

also be modeled as a latent trait. The current proposal examines both reward sensitivity 

and depression in a large (N=300) sample of girls, ranging from 9 to 14 years of age; 

moreover, this sample will be examined two years after the initial visit, so that both 

cross-sectional and longitudinal relationships can be examined. In our pilot data, we have 

focused extensively on the feedback-related negativity (FRN), an electrocortical response 

observed at the scalp as an apparent negativity approximately 300 ms following feedback 

indicating monetary loss compared to gain. Our work suggests that the neural 

differentiation between gains and losses is being driven by a reward-related positive 

potential that is generated in the ventral striatum-part of the basal ganglia that has been 

implicated in reward-related neural circuits. We have found that the FRN relates to fMRIbased measures of striatal response to rewards, as well as behavioral metrics of reward 

sensitivity. Moreover, we have found that the FRN is reduced in both adults and 

adolescents who are more depressed-and have recently found that reduced reward-related 

brain activity can predict changes in depressive symptoms over the course of two years 

among adolescents. The current proposal extends this work into a much larger and 

longitudinal sample, and incorporates multiple measures of reward sensitivity, depressive 

symptoms, and puberty. We will assess: a) the relationship between multiple measures of 

reward sensitivity and depressive symptoms in a large sample that spans adolescence at 

two time points, separated by 2 years (Aim 1); b) normative developmental increases in 

both reward sensitivity and depressive symptoms, especially as a function of pubertal 

stage (Aim 2); c) prospective relations between reward sensitivity and depressive 

symptoms over time, and whether reward sensitivity at the first assessment can predict 

changes in depression two years later (Aim 3); finally, if pubertal changes predicts a 

stronger link between reward sensitivity and later depressive symptoms (Aim 3). A 

number of secondary aims are also evaluated (e.g., specificity to depressive symptoms 

and not anxious symptoms; utility of salivary testosterone as a marker of pubertal stage; 

role of stressful life events). The present study will contribute to the literature on the 

developmental neurobiology of reward, as well as the neurobiological changes related to 

individual differences in depression and risk for depression across adolescence. 
97

Title: The Influence of Estrogen on the Fear Extinction Network in 

Humans

P.I.: Mohammed R. Milad 

Institution: Massachusetts General Hospital 

Grant No.: MH097880-01

Award: $100,000

The prevalence of anxiety disorders is twice as high in women. The reason for this 

eleveated prevalence is unclear, partly because most animal research has used only males, 

and most human research has not considered sex as a variable of interest. This proposal 

will begin to examine the neurobiological basis for these differences by first studying 

how natural fluctuations of estrogen in healthy women may influence the resting-state 

activity and the extinction-induced reactivity of the fear extinction network, including the 

amygdala, hippocampus, and the ventromedial prefrontal cortex (vmPFC). Additional 

experiments will involve exogenous manipulations of estrogen in naturally cycling 

women to see how these manipulations may interact with the functional activation of the 

fear extinction network. Healthy women will participate in a well-established fear 

conditioning and extinction protocol at different points of their menstrual cycle. 

Functional MRI and psychophysiological tools wil be employed to test two overall 

hypotheses: 1) Naturally elevated estrogen levels during the menstrual cycle will 

facilitate the resting-state activity and extinction-induced functional reactivity of the fear 

extinction network, and will be associated with enhanced extinction retention, and 2) 

Exogenous administration of estrogen to women will enhance extinction retention, which 

will be associated with enahnced resting-state activity and extinction-induced functional 

reactivity of this extinction circuitry during extinction recall. Findings from his proposal 

may help develop sex-specific treatments for anxiety disorders, for example by using 

hormonal-based pharmacological adjuncts to facilitate the processes of safety learning 

during therapy. 

National Institute on Minority Health and Health Disparities

Title: Scientific Conference R13

P.I.: Balwant Singh Ahluwalia 

Institution: Howard University 

Grant No.: MD006773-01S1

Award: $1,000

The focus of this tissue oriented conference is to answer pivotal questions regarding the 

higher incidence and characteristics of uterine leiomyomas in African American Women 

(AAW). The conference will feature scientific presentations that address the current state 

of knowledge and identify emerging issues regarding leiomyomas in the AAW and serve 

as a catalyst for discussion during the final session on “New Course for Future Research 

and Directions”. Newer, promising and innovative research that will continue to build 
98

upon and enhance our understanding of the basic pathophysiology of uterine leiomyoma 

will be discussed. Innovations in treatment modalities with an emphasis on impact to the 

female reproductive tract, reproductive potential and quality of life will be presented. The 

target audience includes researchers working in the fields of biomedicine, epidemiology 

basic, clinical and translational science, therapeutics, academic medicine, government, 

industry; physicians, nurses, other healthcare workers and the lay community. All 

participants will be invited to present posters and special area will be assigned for poster 

presentation. The Conference proceedings will be edited by the editorial committee to 

prepare for publication in a peer reviewed journal and the entire contents will be posted 

on the Howard University Web Site. Accreditation Statement: The activity will be 

planned and implemented with essential areas and policies of the Accreditation Council 

for Continuing Medical Education through the Howard University College of Medicine 

Credit Designation Statement. Howard University College of Medicine will designate 

this educational activity for a maximum of 8 credits AMA Category 1 Credits. Physicians 

will only claim credit commensurate with the extent of their participation in the activity.

National Institute of Neurological Disorders and Stroke

Title: NIH Pain Consortium Centers of Excellence in Pain Education 

(CoEPEs)

P.I.: NIDA (coordinating center)

Institution: NIH Pain Consortium, funding 12 centers

Grant No.: 1201100111U

Award: $200,000

The NIH Pain Consortium has established 12 Centers of Excellence in Pain Education 

(CoEPEs), led by the National Institute on Drug Abuse, to develop and disseminate 

curriculum resources to improve medical, dental, nursing, and pharmacy education in the 

assessment, diagnosis, and treatment of pain, while minimizing the abuse of opioid 

medications, an area that current training under-emphasizes. A wide variety of women’s 

health issues will be addressed, including: Migraine and giant cell arteritis-related 

headaches; Hormonally-related headaches associated with menstruation, pregnancy, and 

menopause; Fibromyalgia and/or temporomandibular joint disorders; Stage IV 

endometriosis experiencing pelvic pain and dysmenhorrhea; Post-operative pain in an 

infant who underwent a laparotomy to remove an ovarian cyst; Female breast cancer 

patients and survivors experiencing pain related to or separate from cancer; Pelvic pain of 

unknown etiology; Musculoskeletal pain in a female who may be a victim of domestic 

abuse; End-of-life pain management scenario for a female patient with a 30 year history 

of systemic lupus erythematosus; Irritable bowel syndrome; Neuropathic dental pain, 

atypical odontalgia (phantom tooth pain), and burning mouth syndrome; and Vulvodynia 

and chronic fatigue syndrome.

Title: Neuropathologic Abnormalities Define a Subgroup of Patients 

with CFS
99

P.I.: Benjamin Natelson 

Institution: Beth Israel Medical Center 

Grant No.: NS075653-02

Award: $66,509

Chronic fatigue syndrome (CFS) is a debilitating multi-symptom disorder characterized 

by unexplained and prolonged fatigue, whose diagnosis is currently based on a relatively 

broad clinical case definition. Consequently, the pool of CFS patients included in clinical 

studies of the illness is greatly heterogeneous—a fact that might have impeded research 

progress to date. A major step forward in understanding the pathophysiology of CFS 

would involve reducing this heterogeneity by identifying one or more subgroups of 

patients with different pathophysiological causes of their illness, and then selecting one 

of these subgroups for inclusion into research studies. Over the past few years, we and 

others have provided substantial data supporting the existence of a subgroup of patients 

with a neurobiological cause for their illness, based on stratifying the sample according to 

the absence or presence of comorbid Axis I psychopathology (CFS-no psych or CFS-NP 

and CFS-psych or CFS-P, respectively). Compared to CFS-P patients, the CFS-NP 

patients had more cognitive dysfunction, a higher rate of abnormal cerebrospinal fluid 

(CSF) findings, lower regional cerebral blood flow (rCBF), and higher ventricular CSF 

lactate values. A further complication and limitation of these studies is that each had 

investigated only one brain-related variable, whose utility in separating CFS patients into 

subgroups was limited. The purpose of the present Exploratory/Developmental Research 

Grant (R21) proposal is to rigorously assess and confirm whether patients in the CFS-NP 

group have consistent abnormalities across several different neuropathological 

variables—an outcome that would be expected if this group, in fact, does have distinct 

neurobiological underpinnings. Specifically, in the same subjects, we will (a) assess 

cognitive function using objective neuropsychological testing; (b) conduct biochemical 

analysis of spinal fluid samples obtained by lumbar puncture; and (c) measure rCBF and 

ventricular lactate using magnetic resonance imaging and spectroscopy, respectively, in 

CFS-P and CFS-NP patients. This will allow us to test the hypothesis that CFS-NP 

patients have more abnormalities in these outcome variables than CFS-P patients. Our 

second Aim will use the results from the first Aim in a cluster analysis to attempt 

objective, data-driven classification of the CFS subjects into subtypes, and then compare 

the resulting subgroups based on membership into CFS-NP or CFS-P groups. This aim 

will test the hypothesis that the results of the cluster analysis will identify a group with 

abnormalities across the multiple brain-based variables studied, and this group will be 

constituted of significantly more CFS-NP patients than in other groups.

Title: Brainstem Pain-Modulating Systems in Migraine-Related 

Photophobia

P.I.: Mary M. Heinricher 

Institution: Oregon Health & Science University 

Grant No.: NS082020-01

Award: $300,000
100

Migraine is the most common neurological disorder, and affects over 10% of the 

population in any given year, with over half of these individuals reporting severe 

impairment. For many patients, a severe, even disabling, component of the migraine 

attack is photophobia, yet neuroscientists are just starting to investigate the underlying

neurobiological mechanisms. The present application tests the overarching hypothesis 

that brainstem pain-modulating circuits, already implicated in migraine-related pain, also 

contribute to migraine-related photophobia. This hypothesis is based on the entirely 

unexpected observation that pain-modulating neurons in the rostral ventromedial 

medulla, the final output of an important brainstem pain-modulating system, develop 

photoresponsiveness in animal models of migraine headache, although they do not 

respond to light under normal conditions. In three Specific Aims using the nitroglycerin 

migraine model in the rat, we will document light-evoked activity in identified painmodulating neurons and determine whether this is specific to migraine. We will also 

determine whether pain-modulating systems contribute to light aversion and lightinduced pain enhancement. Finally, we will identify possible pathways through which 

light gains access to pain-modulating systems. The present proposal brings together 

electrophysiological and behavioral approaches to show how light engages painmodulating systems to produce photophobia. These studies will provide insights into the 

neurobiological mechanisms of migraine-related photophobia, fundamental information 

critical for developing new migraine treatments.

John F. Fogarty International Center for Advanced Study in the 

Health Sciences

Title: Vanderbilt University-CIDRZ AIDS International Training and 

Research Program

P.I.: Sten H. Vermund 

Institution: Vanderbilt University Medical Center 

Grant No.: TW001035-14

Award: $25,000

The Vanderbilt University (VU) Center for Infectious Disease Research in Zambia 

(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. We 

contribute research training to both institutional and individual biomedical and behavioral 

research capacities focused on HIV-related research in both prevention and care. The 

VU-CIDRZ training partnership with our 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. We now seek to renew our AITRP with a 

continued focus on Zambia (since 1998), Pakistan (since 1994), India (since 2000), China 

(since 2000), and our newest partnership in Mozambique (VU training partnership since 

2006 and developmental AITRP engagement since 2007). We have completed our older 

training commitments in Mongolia, Jamaica, and Russia and will complete our training 

commitments for Bangladesh upon the graduation of a current doctoral training 
101

(anticipated in 2011). We have restricted our AITRP training partnerships to five focus 

cities in order not to dilute our impact to where we have funded overseas research and 

strong research training partners. At the same time, we have leveraged support in each of 

the five venues such that our AITRP resources will go much further than permitted by the 

grant’s funding alone. We 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 our in-country advanced shortcourses. We believe VU remains an ideal university partner for this initiative for several 

significant reasons The migration of the training program to VU offers the opportunity 

for trainees to receive the absolute highest quality of graduate training and exposure to 

innovative HIV/AIDS/STD/TB related research, resources, and faculty mentors. The 

program is uniquely positioned within the infrastructure of the VU Institute for Global 

Health (VU IGH),directed by Dr. Vermund with its “center-without-walls” philosophy

that nurtures noncompetitive partnerships among and within VU and with partner 

institutions around the globe. We feel that the innovative features of our renewal and our 

proven track record address the unmet needs in international AIDS training.

RELEVANCE (Seeinstructions): The VU-CIDRZ training partnership with our 

international collaborators is designed to strengthen both institutional and individual 

biomedical and behavioral research capacities focused on HIV-related research in both 

prevention and care in developing countries. 

Title: AIDS International Training and Research Program

P.I.: Adaora A. Adimora 

Institution: University of North Carolina at Chapel Hill 

Grant No.: TW001039-14

Award: $25,000

This is the second competitive renewal application for the UNC AIDS International 

Training and Research Program. We 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, we use training to build 

strong ties to key in-country organizations. Trainees with guaranteed “return jobs” in 

these organizations are preferentially selected. Second, our training opportunities build on 

funded research projects and bridge many of the strengths of UNC. Wherever possible we 

combine basic, clinical and epidemiological training and research in order to build critical 

mass. Third, we have used the Fogarty training to promote international research, 

working with many collaborators and funding agencies. Fourth, we 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 we 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, we have looked for opportunities for evolution and innovation. Such 

efforts have been particularly important in the development of a new Department of 
102

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, we are committed to in-country 

leadership and ongoing mentorship after the trainee has completed our program. 

Title: Emory AIDS International Training and Research Program

P.I.: Carlos Del Rio 

Institution: Emory University 

Grant No.: TW001042-14

Award: $25,000

Located in Atlanta, the Emory AIDS International Training and Research Program 

(AITRP) has established itself as an interdisciplinary training environment, that is 

producing highly qualified HIV/AIDS researchers. The collaborating countries of the 

Emory AITRP proposed for this application are Mexico, Georgia, Vietnam, Rwanda and 

Zambia. The specific aims of the research training program include: 1. To build academic 

capacity in partner countries through the support of in-country education and training. 2. 

To build HIV/AIDS research human resource capacity through the support of degreeseeking, 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 our 

trainees to become involved in the evaluation of the impact of a variety of interventions 

that are currently occurring in our collaborating countries such as PEPFAR.

Title: Haiti AIDS Research Training: Models to Implementation

P.I.: Jean William Pape 

Institution: GHESKIO Center 

Grant No.: TW006896-09

Award: $25,000

The goal of GHESKIO-Cornell ICOHRTA training program is to increase capacity in 

integrated clinical, operational, and health services research in support of Haiti’s national 

scale-up of HIV and tuberculosis services. Haiti is the poorest country in the Western 

Hemisphere and has the highest rates of both HIV infection and tuberculosis. It is 

estimated that 3% of the adult population is HIV-infected and that the prevalence of 

tuberculosis is 402/100,000 population (100xUS rates). In response to this epidemic, the 

Haitian Ministry of Health asked GHESKIO to form a national HIV and TB Network, a 

collaboration of 32 public and private health care organizations across the country that is 

charged with “scaling-up” to provide a standardized package of HIV and tuberculosis 

services to 500,000 persons by 2014. The services include voluntary counseling and HIV 

testing, management of tuberculosis and sexually transmitted infections, prevention of 

mother to child HIV transmission, and comprehensive HIV care of children, adolescents,

and adults. The Haitian Ministry of Health has asked GHESKIO (Haitian Study Group 

for the Study of Kaposi’s Sarcoma and Opportunistic Infections) to lead this network 
103

through training, supervision, monitoring and evaluation, and through the conduct of 

operational and health services research. GHESKIO is an international research and 

training institution that has benefited from 25 years of uninterrupted NIH funding and 

research capacity building with Cornell University, and support from the Fogarty 

International Center. GHESKIO is recognized as a center of research excellence, and is a 

member of the NIH HIV Vaccine Trials Network (VTN), the AIDS Clinical Trials Group 

(ACTG) and a recipient of support from the United Nations Global Fund for AIDS, TB 

and Malaria and the President’s Emergency Plan for AIDS relief (PEPFAR). In the 

current proposal, GHESKIO will continue as the primary training institution and extend 

research capacity to other organizations in Haiti that are participating in the GHESKIO 

HIV and Tuberculosis Network. The program will continue to emphasize medium- and 

long-term training in Haiti. Since its inception four years ago the ICOHRTA has provided 

training to 120 Haitian biomedical personnel, all of whom are working in Haiti, providing 

HIV/TB services and conducting operational and health services research. GHESKIO, in 

collaboration with Haitian and International partners, will develop training curricula in 

clinical, operational, and health services research methodology and in ethics, program 

management, and scientific writing. A Masters in Public Health Degree program, 

established with ICOHRTA support, will continue to be offered in Haiti by Quisqueya 

University, in partnership with GHESKIO and Cornell University.

Title: Molecular Epidemiology of Drug Resistance and Population 

Genetic Structure of Plasmodium Falciparum and P. Vivax in 

Yunnan and Hainan, China

P.I.: Fangli Lu 

Institution: Sun Yat-sen University 

Grant No.: TW008151-04

Award: $50,000

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 have 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, our long-term goal of this proposal is 1) to identify singlenucleotide polymorphism (SNP) and characterize the geographic distribution of genetic 

diversity, population structure, and haplotype variability at drug resistant loci of P. 
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falciparum from Yunnan and Hainan, China, 2) to examine the geographic population 

structure, levels of genetic diversity of P. vivax using microsatellite and SNP, and 3) to 

yield valuable information for making more effective malaria control policies in China. 

In the past several years we have developed the molecular methods to study the genetics, 

population diversity, and evolution of malaria parasites, and have done some preliminary 

studies on malaria field isolates from Yunnan and Hainan using genetic markers, thus 

enabling us to study the molecular epidemiology of these important malaria parasites in 

this proposal. The specific aims are to: 1. Determine genetic polymorphisms associated 

with CQ resistance (CQR) in P. falciparum field isolates from Yunnan and Hainan 

provinces, China. 2. Determine the point mutation prevalence in the dhfr (pyrimethamine 

drug resistance) and dhps (sulfadoxine drug resistance) genes associated with SP

resistance in P. falciparum field isolates from Yunnan and Hainan provinces, China. 3. 

Assess the changes of P. vivax genotypes using pvcsp, pvmsp1, pvmsp3-¿ genes, and 

microsatellite markers and determine the geographic structure and specific 

epidemiological characteristics of P. vivax transmission in Yunnan and Hainan, China. 

Title: Tobacco Control Network Among Women in Parana, Brazil

P.I.: Isabel C. Scarinci 

Institution: University of Alabama at Birmingham 

Grant No.: TW009272-01

Award: $100,000

An understanding of women and their tobacco-related issues, as well as the need for the 

development of gender-relevant tobacco control efforts, have been highlighted as 

priorities in landmark guiding documents published in the past few years (e.g., WHO 

Framework Convention on Tobacco Control-WHO FCTC). Brazil is the second largest 

producer of tobacco in the world, and 95% of the tobacco is produced in the three 

Southern states (Paraná, Santa Catarina, and Rio Grande do Sul). Although, historically, 

tobacco use among women in developing countries, particularly Latin America, has been 

relatively low as compared to men, the smoking epidemic is rapidly spreading to women 

in developing countries, and these three Southern states have the highest prevalence of 

women smokers in the country. We have established a Network for Tobacco Control 

among Women in Paraná, Brazil with the purpose of establishing community and 

institutional capacity to promote gender-relevant tobacco control efforts among women 

through Community-Based Participatory Research (CBPR) and training. The goals of the 

network are to reduce tobacco use and exposure to environmental tobacco smoke (ETS) 

among women in Paraná, and to develop a cadre of well-trained researchers who will 

continue to address comprehensive tobacco control strategies at multiple levels. The 

network conducted an epidemiological survey on the prevalence and factors associated 

with tobacco use among women across the State of Paraná. Based on the results, the 

network identified four priorities: (1) to implement policy changes to decrease ETS; (2) 

to understand the health/social issues of women in tobacco farming; (3) to develop and 

evaluate a comprehensive, culturally- and gender-relevant, school-based smoking 

prevention program; and (4) to improve access and delivery of smoking cessation 

programs through the public health system with a particular focus on “light smokers” as
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74.8% of women smokers in our study reported smoking 10 or less cigarettes/day. The 

network is currently addressing the first three priorities, including support for legislation, 

which resulted in Paraná having the strongest indoor tobacco ban in the country. The 

overall goal of this renewal is three-fold: (1) to continue to sustain and strengthen the 

network; (2) to conduct a group randomized controlled trial to assess the efficacy of a 

theory-based, culturally- and gender-relevant Community Health Worker intervention for 

Brazilian women “light smokers” that will augment the smoking cessation programs 

offered through the public health system; and (3) to expand our current Career 

Development and Research Training Program to the other two major tobacco growing 

states in order to develop a cadre of well-trained researchers who will continue to develop 

and implement gender-relevant comprehensive tobacco control strategies at all levels.

Title: Vanderbilt-Emory-Cornell-Duke Consortium for Global Health 

Fellows (VECDor)

P.I.: Sten H. Vermund 

Institution: Vanderbilt University Medical Center 

Grant No.: TW009337-01

Award: $40,000

The Vanderbilt-Emory-Cornell-Duke Consortium (VECDor) brings the substantial and 

complementary expertise of experienced institutions to the Fogarty Global Health 

Fellows Program. The Vanderbilt Institute for Global Health (VIGH) has served as the 

Fogarty International Clinical Research Scholars and Fellows (FICRS-F) Program 

Support Center since 2007, working with 87 partner institutions to nurture 419 

competitively chosen pre- and postdoctoral trainees from the US and from 27 low- and 

middle-income countries (LMICs). Topics have included infectious diseases, cancer, 

heart and lung disease, stroke, diabetes, nutrition, behavioral and mental health issues 

(including substance abuse), women’s and children’s health, ophthalmic disease, oral 

health, neurology, and animal-human health. VECDor’s highly experienced global health 

mentors are already working together in the US and LMIC partner institutions, selected 

as diverse, well-funded research sites in Africa (Kenya, Zambia, Tanzania, Rwanda), 

Asia (India, China, Vietnam), Latin America (Brazil, Mexico), and the Caribbean (Haiti). 

Using a highly efficient support center that maximizes the direction of funds to research 

training, and leveraging multiple sources of financial and in-kind co-funding, we will link 

with more than 68 T32 and other NIH-funded training programs and with minority 

institution partners to select and deploy 80 to 100 US and LMIC trainees with 

outstanding promise for research careers. VECDor will implement a strategic mentoring 

and trainee support plan across the consortium, including a substantial preparation phase 

prior to field deployment and continuing after the research year is completed, to ensure 

the highest quality research publications and scientific meeting presentations, and 

maximum trainee success in obtaining research and career development grants. Research 

themes will address all topic and geographical areas of interest to trainees and NIH 

Institutes and Centers, emphasizing both communicable and non-communicable diseases. 

We will document the Program’s impact through a long-term monitoring and evaluation 

(M&E) plan that tracks the career directions and outputs of all Fellows, using FIC’s 
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CareerTrac system, e.g., future employment, K grants, research grants, scientific 

presentations, and publications. We will further refine our existing web-based tools to 

share knowledge, foster local and global networking, and strengthen and sustain clinical 

research skills among global health fellows and alumni. We have brokered substantial 

institutional and site-based co-funding to leverage NIH resources. VECDor is built on the 

mutual respect of our US and global partners and our collective track record of research 

innovation and mentorship. Combining our extensive recent experience in research 

training program management, robust research funding bases in major diseases of global 

significance, renowned international research training partners and sites, and enhanced 

institutional co-funding commitments, VECDor will continue to nurture key members of 

the global health research workforce of the 21st century, as we have done within the 

incumbent FICRS-F program.

Title: Global Health Fellows and Scholars Research Training

P.I.: Lee W. Riley 

Institution: University of California, Berkeley 

Grant No.: TW009338-01

Award: $40,000

We propose to establish a Support Center (Consortium) involving University of 

California-Berkeley, Yale University, Stanford University and Florida International 

University to train postdoctoral fellows, PhD graduate students, and medical students for 

them to develop a long-term career in global health research. The main objective of the 

program is to generate a new and young cadre of global health researchers, educators, and 

professionals who will be prepared to address the new challenges in global health that 

arise from our constantly changing planet, in particular, those challenges that emerge 

from the world’s burgeoning human settlements known as slums that have developed in 

urban and rural communities of many low and middle-income countries (LMIC). Slumspecific factors associated with chronic, noncommunicable, as well as infectious diseases, 

environmental health hazards, risks specific to women and children, intentional and 

unintentional injuries, and mental disorders are poorly understood, and there are not 

many researchers dealing with these issues. These diseases comprise a large proportion of 

the world’s health problems. Our training program will emphasize a multidisciplinary, 

problem-based approach using slum health as a platform to expose trainees to the new 

concepts, models, and approaches to global health research. The training will be 

conducted at US government-funded field research sites at 10 locations abroad, including 

Central and South America, Sub-Saharan Africa, South Asia, East Asia, and Eastern 

Europe, where the Consortium mentors have been conducting research for more than 3 

years. The Consortium includes a large reservoir of postdoctoral fellows and upper 

division graduate and medical students who will be candidates for the training program. 

The Consortium has made a special effort to identify potential trainees from underrepresented minority groups and it has thus partnered with Florida International 

University, the largest Hispanic-serving institution in the continental US, which also has 

a large pool of African-American students. Thus, this research training program will 

provide an opportunity to draw highly skilled researchers from diverse backgrounds from 
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a wide spectrum of disciplines, who will use the knowledge gained from this program to 

develop their own research agenda to improve the lives of people who are exposed to a 

wide range of interacting health risks that engender new global health challenges.

Title: Fogarty Global Health Fellows Coordinating Center

P.I.: Charles Michael van der Horst 

Institution: University of North Carolina at Chapel Hill 

Grant Nos.: TW009340-01, TW009340-01S4

Award: $190,000

The University of North Carolina, Johns Hopkins University, Morehouse School of 

Medicine, and Tulane University have formed a consortium, based on over 20 years of 

research and training collaboration, to launch the Fogarty Global Health Fellows Program 

(FGHF). This consortium brings together 17 primary research training sites in Africa 

(Ghana, Malawi, South Africa (2), Swaziland, Uganda (2), Zambia), Asia (Bangladesh, 

China (3), India, Thailand) and South America (Argentina, Brazil, Peru). Our proposal 

focuses on more advanced trainees, regional partnerships, multilayered mentoring. Each 

primary training site has a lengthy history of NIH and US government research funding, 

training of US and international research trainees, and on-the-ground faculty mentors, 

many of whom were trained through Fogarty International Center programs. Twelve of 

the proposed training sites are currently part of the Fogarty International Clinical 

Research Scholars & Fellows program. We will preferentially recruit advanced postdoctoral researchers from more than 50 T32 training grants at the affiliated institutions in 

all disciplines of health sciences, as well a early-stage post-doctoral researchers, and 

doctoral and health science students from Schools of Dentistry, Medicine, Nursing, 

Pharmacy, Public Health and Veterinary Medicine at our 4 universities and around the 

US. Trainees from the international sites will be “twinned” with US trainees through 

additional resources including other existing Fogarty training grants and the Gilead 

Foundation to build research capacity at the sites to which the consortium has longstanding commitment. The areas of research focus include a broad range of topics that are 

consistent with the NIH Fogarty 2008-2012 Strategic Plan, recognizing the growing 

importance of non-communicable diseases while continuing the commitment to 

infectious diseases. Trainee applications will be judged on the quality of the research 

proposal, their previous track record, and commitment to a global health academic 

research career. Trainees will be assigned a team of mentors, with at least one senior and 

one junior mentor, who will closely monitor the progress of the trainee and provide onsite supervision. Drawing on existing linkages between sites and training faculty, we will 

enhance regional partnerships in order to provide training and guidance for junior 

mentors. Trainees and their twins will have access to biostatistical and epidemiologic 

consultation from UNC and Tulane faculty for both data analyses and grant writing 

purposes as well as supplemental funding for their research from multiple small grant 

opportunities at UNC. FGHF leverages a unique set of resources, training faculty, and 

sites in order to directly respond to three of the four Fogarty Strategic 2008-2012 Goals: 

bridging the training gap, fostering sustainable research, and building strategic 

partnerships.
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Title: University of California Global Health Institute Program for 

Fellows and Scholars

P.I.: Craig R. Cohen 

Institution: University of California, San Francisco 

Grant Nos.: TW009343-01, TW009343-01S1

Award: $190,000

In response to RFA-TW-11-001, the University of California Global Health Institute 

(UCGHI), including UC San Francisco (UCSF), UC San Diego (UCSD), UC Los 

Angeles (UCLA) and UC Davis (UCD), along with a network consisting of 21 

collaborating international institutions across 14 countries and 5 continents proposes the 

creation of the UCGHI Program for Fellows and Scholars (UCGHI-PFS). Our specific 

aims are: 1) To recruit a diverse group of trainees who are diverse in discipline and 

ethnicity, and who aspire to build successful academic research careers in global health 

focusing on interdisciplinary research; 2) To provide outstanding, interdisciplinary 

education and training in global health in collaboration with 230 faculty mentors from the 

Program, and 21 collaborating well established international institutions; 3) To provide 

each trainee with a rich and enduring mentored research experience that fosters scientific 

and career development in global health research; 4) To develop models of 

interdisciplinary, innovative global health research and training designed to improve 

health for populations around the world; and 5) To broaden and expand the global health 

faculty across the four UC campuses, UCGHI and international partner institutions, and 

strengthen existing global health networks between UCGHI and collaborating 

international institutions. UCGHI-PFS will recruit candidates from a pipeline of 57 T32 

programs, representing 12 of the 15 NIH institutes participating in this RFA. In addition 

to these programs which annually support 160 predoctoral and 208 postdoctoral fellows, 

20% of whom are under-represented minorities, we will recruit international trainees 

from 8 D43 training grants across al four campuses, affiliated schools and international 

partner institutions. For each trainee, 4 principal components include: i) an 11-month, 

hands-on research project on-site with one of our international collaborative partners; ii) a 

strong, interdisciplinary mentored research experience; iii) instruction in global health 

and related topics provided through on-site, and on-line courses; and iv) career 

development to help ensure that trainees attain their short-term career goals and succeed 

in transitioning to the next career stage. These four components are closely interlinked; a 

Leadership Group and campus Steering Committees will ensure they form a seamless, 

integrated program. Innovative aspects include a unified consortium that offers synergy 

by capitalizing upon the UCGHI’s ten campuses, Centers of Expertise and faculty that 

regularly interact and collaborate; faculty mentors offering training across diverse 

disciplines (e.g., medicine, nursing, pharmacy, dentistry, public health, veterinary 

science, oceanography, agriculture, and biological and social sciences); training 

experiences on a wide range of diseases and problems of global health significance; an 

ability to leverage common resources across the four participating UC campuses (e.g., 

UCGHI, CTSAs, CFARs and Research eXchange consortia); and an innovative 

mentoring initiative.
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Title: Northern/Pacific Universities Global Health Research Training 

Consortium

P.I.: Joseph Raymond Zunt 

Institution: University of Washington 

Grant No.: TW009345-01

Award: $40,000

This R25 proposal, the “Northern/Pacific Global Health Research Fellows Training 

Consortium” includes a consortium of four U.S. universities (the Universities of Hawaii, 

Michigan, Minnesota and Washington) and partnerships with universities and research 

institutions in six countries (Kenya, Ghana, Uganda, Peru, China and Thailand). The 

Consortium will be housed within the Department of Global Health at the University of 

Washington. The four U.S. universities have each committed matching funds totaling 

$595,000 to support a second year of fellowship for the most productive fellows and 

additional fellows. The N/P Consortium will (1) implement an enhanced mentoring 

program emphasizing a manual of required, specific commitments and guidelines for 

mentors and mentees; bimonthly Internet-based research-in-progress sessions involving 

all Global Health Fellows and joint participation of mentors for the presenting trainee(s); 

(2) help in “globalizing” existing T32 research training programs, and strengthen and 

broaden the disciplines involved in our Consortium’s global health research programs, by 

actively recruiting senior U.S. fellows from the 161 T32 research training grants of the 

N/P Consortium, and other trainees (e.g. senior Department of Global Health postdoctoral 

fellows of the UW Institute for Health Metrics and Evaluation), (3) promote 

entrepreneurial development of interdisciplinary, cross-institutional, sustainable research 

partnerships, particularly within neglected areas of global health, engaging comentors 

from the academic programs that house the T32 grants from which Global Health 

Research Fellows are recruited; (4) establish a “warranty” for the Global Health Research 

Fellows, beginning with a tried and proven expedited global research project trajectory 

during year one, progressing to presentation and then publication of research, a potential

second year of fellowship funding for the most promising trainees, to assistance 

launching independent careers through further opportunities in new research programs as 

they develop, to ongoing mentoring of alumni in applications for new global health 

grants, such as Fogarty IRSDA K01 grants, ISGHA K02 grants, other K awards, 

including CTSA awards and Foundation awards, to creation of an alumni and mentor 

network involving posting of new publications, funding and job opportunities, and 

potential participation in cross-consortium Global Health Fellows reunions at global 

health conferences. This proposal would provide funding for a total of 12-15 trainees 

each year, depending on the number of second year trainee awards—for a total of 75 

trainees. Including the Fulbright/Fogarty Fellows in Public Health (at least one each in 

Kenya, Ghana and Peru), who will receive the same orientation at NIH and mentoring by 

participants in this proposal, we anticipate at least 90 trainees over the five-year grant 

period.
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National Center for Complementary and Alternative Medicine

Title: Brain-Centered Therapy versus Medication for Urgency Urinary 

Incontinence—A Randomized Clinical Trial

P.I.: Loren Howard Ketai 

Institution: University of New Mexico Health Sciences Center 

Grant No.: AT007171-01A1

Award: $100,000

Brain-Centered Therapy versus Medication for Urgency Urinary Incontinence RCT 

Project Summary/Abstract Urinary urgency incontinence, involuntary urine loss 

associated with a sudden, compelling desire to urinate, is a common and costly public 

health problem without cure. Urgency incontinence increases with age and its sufferers 

are primarily women. These women have severely compromised quality of life from the 

stigma and humiliation of urgency incontinence. They have attendant depression and loss 

of work productivity, income and independence. They must bear the burden of 

medication costs, despite medication’s limited effectiveness. Due to unprecedented 

growth of the U.S. population older than 65, urgency incontinence will consume 86.2 

billion dollars by 2020. Finding successful, durable treatment for this burgeoning public 

health problem is an unmet need. This project will evaluate hypnotherapy treatment to 

meet this need. This proposal will compare efficacy of hypnotherapy to pharmacotherapy 

in urgency incontinence. Preliminary evidence supports pursuit of hypnotherapy in 

urgency incontinence treatment. Patients with functional disorders such as urgency 

incontinence respond differently to physiologic stimulus. This abnormal stress response,

“hyper-vigilance,” is associated with abnormal brain activation on functional brain

imaging. Hypnotherapy offers the hope of modifying this abnormal response in urgency 

incontinence. A case series and our own pilot data support hypnotherapy’s effectiveness 

in urgency incontinence. Therefore, the long term goal of this proposal is to shift focus of 

urgency incontinence treatment towards the brain and away from the peripheral nervous 

system, the target of pharmacotherapy. The objective of this application is to determine 

whether hypnotherapy can be more effective than current pharmacologic therapy of 

urgency incontinence. Its central hypothesis is that hypo-therapy modulates interactions 

between the brain and bladder, providing effective urgency incontinence treatment. This 

hypothesis will be tested pursuing 2 specific aims: 1) Determine whether a mind/body 

therapy (hypnotherapy) is a more effective and durable treatment of urgency urinary 

incontinence than a non-mind/body treatment (pharmacotherapy) 2) Determine whether 

hypnotherapy treatment of urgency urinary incontinence is associated with greater 

modification of limbic cortex activation and connectivity on functional MRI than that 

which occurs following pharmacotherapy. Urge incontinent women (N=152) will be 

randomized to medications or hypnotherapy and evaluated at months 2, 6 &12. Sixty 

women will undergo imaging before and after treatment. The rationale for the proposal is 

based on work which suggests that brain activation is abnormal in subjects with urgency 

incontinence, that urgency incontinence responds to hypnotherapy, and that the hypnotic 

state affects sites of abnormal brain activation. This proposal is significant because it 

seeks to treat urgency incontinence, a growing public health problem, with hypnotherapy, 

a mind/body intervention. This novel approach uses hypnotherapy to treat urgency 
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incontinence and offers innovative use of brain imaging to elucidate hypnotherapy’s 

mechanism of action and shifts the treatment paradigm from the bladder to the mind.