Specialized Centers of Research on Sex Differences

Institution: Yale University
Principal Investigator: Sherry McKee, Ph.D.

The Yale SCOR is bringing together leading basic and clinical science experts to establish an interdisciplinary, translational, cross-species program of research aimed at identifying novel therapeutics to address the critical health disparity that female smokers face. Tobacco use is the leading cause of preventable morbidity and mortality in the United States. Women, compared to men, have poorer rates of smoking cessation and exacerbated health risks, and FDA-approved medications for smoking cessation may not be as effective for women or may have emerging limits due to side effects. However, few attempts have been made to develop gender-sensitive smoking cessation treatments. The considerable body of data suggesting that women are more likely to smoke to regulate negative affect and stress while men are more likely to smoke for the reinforcing properties of nicotine suggests an important direction in the development of a new approach to smoking cessation treatments. Using both preclinical and clinical strategies, our interdisciplinary team will probe the noradrenergic system's effects on stress-reactivity and nicotine reinforcement, hypothesizing that (a) different brain systems modulated by noradrenergic activity are activated by smoking in women and men, and (b) guanfacine (an alpha-2a noradrenergic agonist) can preferentially target these gender-sensitive systems to improve smoking cessation outcomes. Using a translational approach with an interdisciplinary team effort, we are proposing three projects that will have interrelated and shared goals, with each providing unique contributions to the development of gender-sensitive therapeutics. This new application will catalyze Yale's significant resources to support interdisciplinary and translational science in women's health to pursue extremely timely scientific findings that could represent a breakthrough in our understanding of treatments for a public health problem that affects millions daily. The specific aims and objectives of the Yale SCOR are the following: 1: Evaluate the role of the noradrenergic system and its interactions with cholinergic and dopaminergic systems in stress-induced smoking relapse and nicotine-based reinforcement, and use these findings to inform and expedite the development of gender-sensitive therapeutics for smoking cessation. 2: Mentor junior investigators in conducting interdisciplinary translational research on tobacco use and women's health through training opportunities, including "clerkships" with SCOR PIs and pilot funding. 3: Be a national resource to invigorate and galvanize the study of sex and gender differences in relation to smoking by providing expert consultation; supporting faculty training awards; mining national data on gender, smoking, and health outcomes to inform health policy; and expanding our current program of local and national community outreach.

Institution: University of Colorado Anschutz Medical Campus
Principal Investigator: Wendy Kohrt, Ph.D.

The overarching objective of the University Of Colorado Anschutz Medical Campus Specialized Center Of Research on Sex Differences (UCAMC SCOR) is to develop an interdisciplinary and translational research program to advance the understanding of the bioenergetic and metabolic consequences of the loss of gonadal function. There is compelling evidence from studies of laboratory animals that gonadectomy causes a dramatic decrease of 30%—80% in spontaneous physical activity in males and females. Even more intriguing is the observation that this results in excess weight gain, a marked increase in visceral fat, and metabolic dysfunction in female animals but not males. If such findings are relevant to humans, the age-related decline in gonadal function may be an important independent determinant of disease risk. Moreover, this would be expected to have a greater adverse effect on the health of women than of men, because the loss of gonadal function occurs at an earlier age in women. There will be three SCOR research projects to advance novel research in this area: (1) Project 1 (clinical): Bioenergetic and Metabolic Consequences of the Loss of Ovarian Function in Women (PI: W. Kohrt); (2) Project 2 (preclinical): Effects of Pre-existing Obesity on Consequences of the Loss of Ovarian Function (PI: P. MacLean); and (3) Project 3 (basic): Sex Hormones Differentially Regulate Production of Distinct Adipocyte Populations (PI: D. Klemm). The Administrative Core will contribute to the success of the SCOR by (1) providing scientific leadership for a focused translational and transdisciplinary research program on the consequences of the loss of gonadal function; (2) monitoring the productivity of SCOR Research Projects; (3) expanding the scope of the SCOR through an Ancillary Projects program; (4) expanding the cadre of investigators conducting research on the gonadal regulation of energy balance and metabolism through the Ancillary Projects program; (5) integrating activities of the SCOR with closely partnered programs at UCAMC, including the Center on Aging, the BIRCWH program, the Center for Women's Health Research, the Nutrition and Obesity Research Center, the Women's Reproductive Health Research Career Development program, and the Colorado Clinical and Translational Science Institute; (6) providing biostatistical and data management support for the SCOR research projects; and (7) providing administrative support for financial oversight, regulatory oversight, and scheduling and general management of SCOR activities.

Institution: Northwestern University (NU)
Principal Investigator: Andrea Dunaif, M.D.

The NU SCOR explores the overarching hypothesis that genetic variation resulting in hyperandrogenemia produces the phenotypic features of polycystic ovary syndrome (PCOS) by androgen programming in utero as well as by ongoing androgen actions at critical developmental periods and in the adult. We have found sex-specific metabolic phenotypes in PCOS families, mapped several PCOS susceptibility genes, developed animal models of androgen programming, and discovered that androgen-mediated estrogen resistance is an important mechanism for these androgen actions. It is clear that the genes for PCOS so far identified do not explain the high heritability of this disorder. We will investigate the mechanisms for this deficit in heritability as well as the molecular mechanisms by which estrogen resistance can produce obesity and metabolic abnormalities in PCOS. Our strategy for achieving the SCOR objectives is to directly investigate the genetic, epigenetic, and hormonal determinants of PCOS in three highly interactive, synergistic, and interdisciplinary projects: Projects 1 and 2 are clinical research projects and Project 3 will utilize a novel nonhuman primate model. Although each project is discrete, the proposed SCOR as a whole will continue to comprehensively investigate novel mechanisms for the pathogenesis of PCOS. Project 1 will test the hypothesis that rare genetic variants will account for much of the deficit in heritability of PCOS. We predict that we will identify rare variants in pathways implicated in the pathogenesis of PCOS in mapping of common variants, such as TGF B signaling, Wnt signaling, insulin signaling, gonadotropin action and extracellular matrix, as well as rare variants in genes in novel pathways. Project 2 will test the hypothesis that a significant component of the heritability of PCOS is due to epigenetic changes, including variation in methylation patterns, that these changes in methylation patterns correlate with changes in expression patterns, and that these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. Project 3 will develop a novel nonhuman primate (marmoset) model of diet-induced obesity to test the hypothesis that androgenic programming of metabolic features of PCOS is mediated by induction of resistance to the actions of estradiol in target hypothalamic neurons that modulate energy homeostasis. These studies are extremely innovative, highly synergistic, and likely to have a major impact on the field through elucidating the pathogenesis of PCOS and its metabolic phenotypes.

Institution: University of Michigan, Ann Arbor
Principal Investigator: John O. DeLancey, M.D.

Although it has been known for millennia that many young women who give birth vaginally will suffer from disabling pelvic organ prolapse later in their lifespan, the factors linking these two events remain a mystery. Of the 3 million women who deliver vaginally each year, 300,000, or 1 in 10, will later require surgery for pelvic floor dysfunction due to their unique sex-determined role in reproduction. Our discovery of birth-induced levator ani muscle injury and its strong relationship to prolapse has identified a key connection between birth and prolapse. Ignorance of how birth-induced injury occurs and how it produces subsequent prolapse has blocked efforts to improve prevention and treatment. In this application we seek to continue SCOR support for our broadly interdisciplinary sex-differences research group representing four schools and two institutes. The group has won 10 awards in the last 4 years for our discoveries and now seeks funding to begin to translate these insights into improved prevention at birth and strategies for better treatment. Project 1, "Birth Biomechanics," will test hypotheses concerning basic mechanisms of levator ani injury during vaginal birth to identify specific situations that may increase or decrease injury risk. Project 2, "Injury Extension," will determine whether minor clinically insignificant levator injury after first birth extends to a clinically significant tear during second birth. Because a second birth doubles the risk of genital prolapse, this event offers the opportunity of preventing injury and their sequelae later in life. Project 3, "Muscle-Ligament Dynamics," will establish the interaction between birth-related levator muscle injury and the properties of the uterovaginal supporting ligaments associated with prolapse. Core A, "Administrative/Human Subjects," integrates and supports the interdisciplinary team and provides project support by recruiting subjects, compiling and analyzing data, and protecting subject safety. Core B, "Biostatistics/Measurements," provides statistical and technical support for the projects along with integrated analysis for 2- and 3-dimensional spatial data gathered across projects. It will prepare data for presentation, publication, subject safety analysis, and, eventually, public use. Core C, "Translation/Mentorship," will foster insight dissemination and drive investigator development. This SCOR will produce translational insights to reduce the sex-determined consequences women suffer from their unique role in reproduction. It will establish the scientific basis for new strategies to improve treatment, identify important prevention opportunities, and train a new generation of researchers.

Institution: Mayo Clinic
Principal Investigator: Virginia Miller, Ph.D.

Establishing a Specialized Center of Research on Sex Differences (SCOR) at Mayo Clinic is consistent with Mayo's strategic plan for research to best serve every patient, every day, through personalized medicine. Sex differences research is integral to personalized medicine. Cardiovascular disease and cognitive decline are two related conditions disproportionately affecting men and women across their lifespan with distinct differences in manifestations, responses to treatments, morbidity, and mortality. The overarching theme of this interdisciplinary SCOR is to understand how female-specific conditions associated with major hormonal shifts, hypertensive pregnancy disorders, and menopausal estrogen deficiency or menopausal hormone therapy affect cerebrovascular function and cognition in women. Three individual but interrelated projects will investigate the overarching theme. Project 1 will test the hypothesis that a history of hypertensive pregnancy disorders is a risk factor for all-cause and cardiovascular mortality, future cardiovascular disease, and cognitive impairment by using a population-based approach. Cohorts selected from the Rochester Epidemiology Project (REP) will be evaluated prospectively for cerebrovascular responses and cognitive function. Project 2 will investigate the neuroprotective effects of estrogen treatment on imaging markers of cognitive health and cognitive performance in women who were treated with estrogens compared with placebo during early menopause. Early menopause is considered the "window of opportunity" for estrogen treatment. This project leverages the cohort of the ongoing Kronos Early Estrogen Prevention Study (KEEPS). Project 3, using cohorts defined in Projects 1 and 2, will define cerebral microvascular dilator capacity, characterize the thrombotic potential of blood-borne microvesicles and platelets, and define relationships among those characteristics with cerebral microvascular vasodilator capacity and changes in brain structure and cognition. An administrative core will support operations and quality control, and a clinical analytical core will provide standardized subject recruitment, data management, and analysis for all three projects. The SCOR is highly responsive to the RFA because it addresses specific sex differences underpinning diseases affecting persons through life transitions, it integrates clinical and basic research, and it uses unique resources at Mayo Clinic. This project involves novel technical approaches of imaging and blood-soluble markers to mechanistically approach disease processes. Furthermore, the defined infrastructure and cohorts will provide the basis for future research on sex differences. Viewing research and medical delivery through a "sex-based lens," with attention to an individual's sex chromosomal complement and hormonal status, is fundamental to personalized care. The SCOR on Sex Differences at Mayo Clinic will facilitate incorporation of sex determinants of health, disease, and treatments across the research and clinical enterprise. In addition, the SCOR investigators will disseminate sex-differences research for specific and general national and international audiences.

Institution: University of Minnesota, Twin Cities
Principal Investigator: Marilyn Carroll, Ph.D.

The goal of this SCOR is to take an interdisciplinary approach to studying an emerging and potentially important interaction between sex differences, hormonal status (e.g., progesterone—PRO), impulsivity, and drug-motivated behavior that could have important consequences for reducing two devastating forms of drug abuse, cigarette smoking and cocaine abuse. The central hypothesis is that reducing impulsivity will reduce drug-seeking behavior. Progesterone reduces impulsivity, and combined with drugs that have similar effects (e.g., atomoxetine—ATO), significant reductions in nicotine and cocaine abuse may be achieved. PRO will also be tested in combination with drugs that show some effect for nicotine dependence, varenicline (VAR) in the animal project. Based on a growing literature on sex differences in drug abuse, there may be sex differences in the effect of single and combined treatments. The following are the specific aims of the SCOR: (1) Investigate sex differences in the effect of exogenous PRO compared to placebo on impulsivity and smoking cessation in clinical Project 1. (2) Study sex differences in the effect of exogenous PRO vs. placebo in combination with ATO vs. placebo on impulsivity and relapse to cocaine abuse in clinical Project 2. (3) Examine sex differences in an animal model of nicotine and cocaine relapse and impulsivity for nicotine or cocaine in rats treated with PRO alone and in combination with ATO and VAR. Another goal is to study endogenous PRO effects on nicotine or cocaine self-administration in pregnant rats during gestation (high PRO) and lactation (low PRO) compared with males and nonpregnant females. This SCOR allows for an interdisciplinary and translational approach to accomplishing these aims. It also offers economic efficiency, an opportunity to exchange ideas and approaches with others who are involved with the SCOR.

Institution: Washington University in St. Louis
Principal Investigator: Scott Hultgren, Ph.D.

No abstract provided for this grant.

Institution: University of Pennsylvania
Principal Investigator: C. Neill Epperson, M.D.

It is well established that childhood adversity is one of the most potent predictors of adult affective disorders, particularly among women. Further, an important dissociation has been reported for a subgroup of women who experience early life adversity but do not present with adult disease, suggesting that there may be resiliency factors important in disease protection or amelioration. In fact, the availability of a caring and stable parent or guardian has been shown to be one of the most important aspects that distinguish between positive and negative outcomes in abused individuals. We propose that one vital contributor to the increased risk for major depressive disorder (MDD) in women, and propensity for other affective disturbances at specific reproductive time points, is the programming effect of prepubertal adversity on dysregulation of hypothalamic pituitary adrenal (HPA) activity and ovarian steroid responsiveness across the lifespan. It is well documented that from puberty to the late perimenopause, MDD and several anxiety disorders are more common in females than males. Moreover, periods of hormonal flux across the female lifespan are associated with increased risk for affective disturbance: the premenstruum (premenstrual dysphoric disorder), the postpartum (onset/relapse bipolar disorder, MDD), and the perimenopause (depression symptoms and MDD). The goal of the scientific projects in this SCOR proposal is to determine how the experience of prepubertal adversity reprograms the brain toward stress dysregulation, and how this intersects with periods of dynamic hormonal flux across the life span, including pregnancy (Projects 1 and 3) and aging (Projects 2 and 3). In addition, mechanistic epigenetic studies will examine sex differences in response to stress during this sensitive window of brain maturation (Project 3). SCOR funding would harness the respective expertise of Drs. Epperson and Bale in behavioral and molecular models of stress and reproductive neuroendocrinology, psychophysiology, and neuroimaging, to create the Penn Center for the Study of Sex and Gender in Behavioral Health. The center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research.

Institution: Medical University of South Carolina

Principal Investigator: Kathleen Brady, M.D., Ph.D.

The establishment of the Medical University of South Carolina (MUSC) SCOR in 2002 provided a critical impetus to engage the research community in more sex- and gender-based research. MUSC had strength in translational, interdisciplinary research on addictions, but no sex- or gender-specific focus. In addition, the SCOR was the first women's health research initiative on the MUSC campus. The visible, campus-wide collaborations of SCOR investigators, combined with the institutional support of the SCOR pilot project program, have considerably increased sex- and gender-based research at MUSC. Close collaboration with the MUSC BIRCWH program, which was awarded in 2007, further enhanced campus-wide, interdisciplinary collaborations focused on women's health. We have begun collaborations with SCOR programs at other universities in order to maximize the scientific output from the ORWH investment in the SCOR initiative by sharing resources and combining data. During the renewal period, our core scientific projects will continue to focus on sex and gender differences in the relationship between addiction and stress response by using emerging technology in closely aligned clinical and basic science projects. The overarching goals of the SCOR center will focus on supporting and improving the translational scientific collaborations of the core and pilot research projects, catalyzing further growth of interdisciplinary sex- and gender-based research on the MUSC campus and creating strategic partnerships to enhance the translation and dissemination of SCOR findings and other relevant research to improve the health of women and girls. Center funding has allowed us to (1) increase interdisciplinary sex- and gender-based research on the MUSC campus; (2) bring together institutional and scientific leadership to form a high visibility operational unit focused on research in women's health; (3) establish infrastructure to support efficient operations, integration, and stability; (4) coalesce a group of senior investigators to integrate their scientific expertise and research skills to advance sex- and gender-based research; (5) attract and train new and junior investigators in sex- and gender-based research; (6) support the development and testing of innovative ideas and new technology; and (7) provide a supportive training environment for basic and clinical researchers interested in sex- and gender-based research. The next funding period will allow us to build on these accomplishments, expand our research program utilizing innovative techniques and novel compounds, increase cross-SCOR collaborations, enhance outreach and dissemination efforts, and attract new investigators. Our SCOR, with a truly interdisciplinary and translational focus on sex and gender issues in addictions and stress response, is prepared to work collaboratively with other SCOR colleagues towards the vision, goals, and objectives outlined in the 2010 ORWH Strategic Plan.