ORWH and partnering institutes, centers, and offices (ICOs) are excited to announce the awardees for the R01 and R21 Notices of Funding Opportunities (NOFOs), Understanding Chronic Conditions Understudied Among Women, which requested research applications on chronic conditions that affect women and individuals assigned female at birth. These awards will fund research on chronic conditions that are understudied among women and/or that disproportionately affect populations of women who are understudied, underrepresented, and underreported in biomedical research. ORWH’s partner ICOs include the National Institute on Aging, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Office of Autoimmune Disease Research in the Office of Research on Women’s Health, Office of Behavioral and Social Sciences Research, and Office of AIDS Research. 

R01 Awardees 

	Regenerative Biomaterial for Combating Genitourinary Syndrome of Menopause Marianna Alperin, M.D., M.S. University of California, San Diego Administering IC: National Institute on Aging Genitourinary syndrome of menopause (GSM) and the associated condition of vulvovaginal atrophy negatively impacts the quality of life of millions of perimenopausal and menopausal women world-wide. Despite its high prevalence and interference with healthy aging, current treatments for GSM are suboptimal, with many issues related to accessibility or long-term efficacy. The proposed research will determine whether a minimally invasive, low-cost, acellular biomaterial with modular delivery mechanism can reverse pathological changes in all vaginal tissue layers and therefore restore a healthy vaginal phenotype.
	Heavy Menstrual Bleeding, Progestin Treatment in Bleeding Disorders Study Maureen Katherine Baldwin, M.D., M.P.H. Oregon Health & Science University Administering IC: National Heart, Lung, and Blood Institute Heavy menstrual bleeding is a frequent and life-altering problem for adolescents and young adults with heritable bleeding disorders, but this population has previously been excluded from research on treatments. In this clinical trial, the proposed research will compare two commonly used treatments that are successful for menstrual suppression in individuals without heritable bleeding disorders—52 mg levonorgestrel intrauterine device (LNG-IUD) and norethindrone acetate (NETA). The bleeding outcomes, satisfaction, hemostatic parameter changes, and patient-reported quality-of-life measures at baseline and through 6 months of treatment of LNG-IUD will be studied and compared to a control group without a bleeding disorder, with the goal of determining the benefits and expected outcomes of these treatment options for this population.
	Resistant Starch Treatment of Polycystic Ovary Syndrome: Impact on Cardiometabolic Dysfunction and the Gut Microbiome Anuja Dokras, M.D., MHCI, Ph.D. University of Pennsylvania Administering IC: National Heart, Lung, and Blood Institute This research project aims to improve treatment options for women with polycystic ovary syndrome (PCOS), which is the most common endocrine disorder affecting premenopausal women worldwide. In addition to infertility and pregnancy complications, women with PCOS often present with obesity, insulin resistance, and dyslipidemia that result in chronic diseases such as type 2 diabetes and cardiovascular disease. Understanding how treatment with resistant starch influences cardiometabolic function and the gut microbiome in PCOS may provide a pragmatic, low-cost treatment for women with this disorder and reveal whether modulation of the microbiome provides novel therapeutic options for PCOS.
	Prospective Health Impacts of Chronic Binge Eating Disorder in Hispanic Older Women Living with Food Insecurity Lisa M. Kilpela, Ph.D. University of Texas Health Science Center Administering IC: National Institute on Aging Older Hispanic/Latina women living with food insecurity are at very high risk for medical conditions; however, they have been understudied in medical research. Chronic binge eating disorder (BED) worsens risk for multimorbidity and may be particularly detrimental for older Hispanic/Latina women living with food insecurity. This study will provide critical information about the prospective impacts of BED in older Hispanic/Latina women living with food insecurity that can be used to inform future treatment efforts and policy changes.
	The Impact of Structural Racism During Pregnancy on Future Cardiopulmonary Health Alison Lee, M.D. Icahn School of Medicine at Mount Sinai Administering IC: National Heart, Lung, and Blood Institute The link between lung health and cardiovascular disease, the leading cause of death in women in the United States, is well established, and pregnancy is a critical window to intervene on racial-ethnic inequities in the life course of chronic disease risk in women. Exposure to place-based structural racism may result in a pro-inflammatory state during pregnancy and impair postpartum cardiopulmonary health, setting the stage for future chronic disease risk. To better understand the mechanisms of action and effect of place-based structural racism during pregnancy on future cardiopulmonary health, a mixed-method longitudinal study of 440 underrepresented and understudied Black, Hispanic, and Asian women will be conducted.
	Multi-omic Characterization of Chronic Obstructive Pulmonary Disease in Females  Dajiang Liu, Ph.D., M.A. Pennsylvania State University Administering IC: National Heart, Lung, and Blood Institute Chronic obstructive pulmonary disease (COPD) is one of the leading risk factors for death. Currently no therapy exists that can reduce mortality or slow down the progression of the disease. Women tend to have more severe disease outcomes, and the prevalence and mortality rates in women are increasing. Multi-omic studies of COPD can reveal disease etiology and guide the development of novel sex-specific biomarkers.
	Pubovisceral Muscle Enthesis Injury: A Bioinspired Approach to Repair Pamela Ann Moalli, M.D., Ph.D.   University of Pittsburgh Magee-Womens Hospital Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development Avulsion of the pubovisceral muscle from the pubic bone at vaginal birth is one of the primary mechanisms leading to the development of pelvic organ prolapse later in life. However, this injury is largely overlooked because there are currently no strategies for repair. This research study proposes to define the pathological changes that follow avulsion and physiologic recovery, to inform the design of novel and effective therapeutic solutions that will benefit women worldwide.
	A Sex-Biased Obesity Gene on the X Chromosome Karen Reue, Ph.D. University of California, Los Angeles Administering IC: National Institute of Diabetes and Digestive and Kidney Diseases Women differ in the development of many cardiovascular disease (CVD) risk factors including obesity. CVD mortality in the population has decreased in the past 40 years, but women aged 35–54 have experienced greater rates of hospitalization, and the incidence of CVD in women over age 60 has outpaced that in men. This research study will examine an identified specific gene on the X chromosome that promotes fat storage and will characterize its effects in fat cells at different points in the female lifespan.

R21 Awardees 

	Clinical Assessment of Radiotherapy-Induced Vaginal Toxicity with Multiparametric Ultrasound Imaging Mark T. Burgess, Ph.D. Sloan Kettering Institute on Cancer Research Administering IC: National Cancer Institute Radiation-induced vaginal toxicity is a common side effect of pelvic radiotherapy, and no clinical tools exist for objective, quantitative evaluation of vaginal health. The goal of this research project is to develop a system and methodology for multiparametric ultrasound-based assessment of vaginal toxicity in the acute and late stages following radiotherapy.
	Examining the Impact of State Laws on Intimate Partner Violence Maureen Vanessa Dalton, M.D., M.P.H.   University of Michigan, Ann Arbor Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development Intimate partner violence (IPV) is common, with greater than 7% of U.S. women reporting physical or sexual violence, and/or stalking in the past year. Over half of women experiencing IPV are victimized multiple times over multiple years, therefore meeting the definition of a chronic condition. This proposal seeks to characterize the impact of state law on rates of IPV and IPV-related health outcomes.
	Noninvasive and Early Detection of Endometriosis Using a Biological Neural Circuit-Based Novel Gas Sensor Asgi T. Fazleabas, Ph.D. Michigan State University Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development There is a critical need for noninvasive and robust endometriosis detection technologies. Although exhaled breath-based endometriosis detection can offer those advantages, exhaled breath-based disease diagnosis has not been implemented in clinical settings, primarily because of the lack of sensitivity and reliability of existing engineered gas sensors. This proposal aims to systematically validate and quantify the performance of a novel olfactory neuron-based gas sensor for early and robust detection of endometriosis using 2-D cell cultures and 3-D organoids, and in a mouse model of endometriosis.
	Single Cell Analytics and Drug Discovery at the Endometrial-Myometrial Junction in Symptomatic Adenomyosis Linda Giudice, M.D., Ph.D. University of California, San Francisco Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development Adenomyosis is a common, chronic gynecologic disorder in which the uterine lining migrates into the myometrium, causing severe menstrual cramps, bleeding, and subfertility. Its pathogenesis and pathophysiology are poorly understood and understudied, and because current medical and surgical therapies are suboptimal, new and effective therapies are needed. This proposal will conduct a single cell transcriptomic and spatial proteomic analysis of the three contiguous endometrial-myometrial junction compartments and a transcriptome-based computational drug-repurposing strategy, with the goal of identifying new and repurposed drugs through signature reversal that together are anticipated to inform mechanisms of adenomyosis pathophysiology and novel therapeutic strategies to mitigate adenomyosis-related symptoms.
	Risk Factors for and Consequences of Endometriosis Among Black Women   Holly Harris, Sc.D., M.P.H. Fred Hutchinson Cancer Center Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development Endometriosis is a common and debilitating gynecologic disorder that affects approximately 10% of persons born with female reproductive organs. To date, almost no research has been conducted on risk factors for or consequences of endometriosis among Black women. This is a significant gap, because many established risk factors for endometriosis differ in their prevalence between Black and White women. This study will be the first-ever study on risk factors and consequences of endometriosis among Black women.
	Heat Therapy to Improve Functional Performance in Heart Failure with Preserved Ejection Fraction Daniel Hirai, Ph.D. Purdue University Administering IC: National Heart, Lung, and Blood Institute Heart failure with preserved ejection fraction (HFpEF) disproportionately affects older women, but very few effective treatments are currently available. The goal of this proposal is to evaluate the benefits of home-based heat therapy on physical capacity and quality of life in older women with HFpEF. Because this intervention is noninvasive, nonpharmacological, and widely accessible, there is high potential for this work to rapidly translate into clinical practice and result in significant improvements in patients’ lives.
	Sex-based Study of Chronic Hypoxia-Related Vulnerability to Depression: Age Effects Shami Kanekar, Ph.D. University of Utah Administering IC: National Institute on Aging In aging, major depressive disorder is linked to systemic inflammation, cognitive deficits, and treatment resistance, with women being highly susceptible. In an animal model, this research study will test the impact of sex and age on hypobaric hypoxia-induced depressive, anxiety, and cognitive symptoms. Because rates of antidepressant treatment resistance increase with aging, the impact of age and sex will be addressed on the antidepressant-like efficacy of selective serotonin reuptake inhibitors (SSRIs) and the bioenergetic compound cyclocreatine, under conditions of chronic hypobaric hypoxia.
	Targeting Estrogen-Sensitive Hypothalamic Neurons to Reverse Frailty in Aging Females William Krause, Ph.D. University of California, San Francisco Administering IC: National Institute on Aging Sex differences in the maintenance and physiological response to physical activity are predicted to contribute to differences in frailty risk and progression between aging women and men. Using a recently developed gene engineering strategy that activates neurons responsible for driving physical activity in female mice, this research study will determine whether increasing daily activity levels ameliorates frailty phenotype, and whether these health and longevity benefits are correlated with changes in liver output.
	Antibody Bound Bacteria During HPV Infection and Cervical Dysplasia Stephanie Langel, Ph.D. Case Western University Administering IC: National Cancer Institute Despite the clear association between high-risk human papillomavirus (HR-HPV) and cervical cancer, the reasons why some women clear HPV infection, while others suffer from chronic infection that leads to cervical dysplasia and cancer, are poorly understood. Evidence is emerging that the vaginal microbiome plays an important role in this process; however, the mechanisms linking vaginal bacteria with host responses, specifically antibody responses, to HPV infection and cervical neoplasia progression are underexplored. This project will study the role of antibody bound and unbound bacteria and associated bacterial functions in women with different HPV infection status and cervical dysplasia pathology.
	CD38 Intensifies Immune Activation in Women Living with HIV Poonam Mathur, D.O. University of Maryland, Baltimore Administering IC: Eunice Kennedy Shriver National Institute of Child Health and Human Development Worldwide, the more than 52% of women living with HIV (WLWH) experience earlier onset of non-AIDS comorbidities (e.g., diabetes and heart disease) and increased mortality compared to men living with HIV (MLWH), despite viral suppression with antiretroviral therapy. The underlying cause for this difference is likely increased HIV-induced immune activation and inflammation in WLWH compared to MLWH. The goal of this proposal is to demonstrate that CD38, a T cell marker of immune activation in HIV infection, plays a role in chronic inflammation in WLWH and is a potential therapeutic target to decrease morbidity and mortality in WLWH.
	Leveraging Sexual Dimorphism to Predict Cardiac Remodeling and Enhance Treatment in Women with Severe Aortic Stenosis Farhad R. Nezami, Ph.D. Brigham and Women’s Hospital Administering IC: National Heart, Lung, and Blood Institute Women with severe aortic stenosis face delayed diagnosis, undertreatment, and higher mortality rates compared to men, highlighting the need for improved diagnostics and treatment strategies for female patients. By integrating innovative medical image processing and computational modeling methods, this project aims to gain sex-differentiating insights into cardiac remodeling and dysfunction in severe aortic stenosis among women, with the goal of enhancing treatment outcomes. This research aims to serve as a basis for guiding clinicians in patient selection, optimizing surgical timing, and ultimately enhancing survival rates for female patients with aortic stenosis.
	Concurrent Eradication of Pathogenic Plasma Cells and Their Precursors in Systemic Lupus Erythematosus Srividya Swaminathan, Ph.D. Beckman Research Institute/City of Hope Administering IC: National Institute of Arthritis and Musculoskeletal and Skin Diseases Abnormal autoantibody-producing B-cell subsets, including plasma cells, are a major driver of systemic lupus erythematosus (SLE). Specific eradication of pathogenic B cells in SLE poses significant clinical challenges. The proposed experiments will solidify blocking the synthesis of the long isoform of the prolactin receptor as an effective approach to specifically eradicate abnormal plasma cells and their precursors without affecting their normal counterparts in patients with SLE.
	Changes in Cardiometabolic Tissue Gene Regulation and Omics Profiles with Menopause Elizabeth Theusch, Ph.D. University of California, San Francisco Administering IC: National Institute on Aging Extensive changes occur due to menopause that can put women at greater risk for heart attacks, diabetes, and related diseases, but the reasons why are not well understood. This research study proposes the use of a chemical that is toxic to follicles in mouse ovaries to simulate menopause, compare it to control female and male mice, and investigate how genes are turned off and on in various organs throughout the body and then how estrogen treatment reverses these changes. Together with comparisons between samples from premenopausal versus postmenopausal women, these findings could identify genes that change with menopause, facilitating more precise prevention and intervention strategies for cardiovascular disease in midlife women.