"Sex" refers to biological differences between females and males, including chromosomes, sex organs, and hormonal profiles. "Gender" refers to socially constructed and enacted roles and behaviors which occur in a historical and cultural context and vary across societies and over time. All individuals act in many ways that fulfill the gender expectations of their society. With continuous interaction between sex and gender, health is determined by both biology and the expression of gender.

As consideration of these variables is critical to the accurate interpretation and validation of research findings that affect the various aspects of women's health, ORWH developed a program to catalyze exploratory research on sex/gender differences by providing an administrative supplement to ongoing NIH-funded research. Since the program began in 2013, ORWH has invested almost $18 million in supplemental funding by supporting close to 200 grantees across most Institutes and Centers at NIH to explore research on sex/gender differences in preclinical and clinical studies. To further advance this important but understudied area of research, ORWH has pledged $5 million for 2016. This progressive approach has resulted in greater awareness of the need to study both sexes, demonstrate how research can incorporate sex, and reinforce the value of taking it into account as these studies yield results.

The funded projects span a wide array of science from bench to bedside, including basic immunology, cardiovascular physiology, neural circuitry, behavioral health, and omics. The 2016 funding opportunity announcement (PA-16-066) stated that the proposals for supplemental funding must demonstrate at least one objective from Goals 1-3 of the NIH Strategic Plan for Women's Health Research. Other areas of interest include the study of both male and female subjects, and the comparison of their outcomes.

  • Goal 1: Increase sex differences research in basic science studies
  • Goal 2: Incorporate findings of sex/gender in the design and development of new technologies, medical devices and therapeutic drugs
  • Goal 3: Actualize personalized prevention, diagnostics and therapeutics for girls and women

Find program summaries by NIH institute below.

Fiscal Year 2015

  • Berries and Bone 
    Principal Investigator: Connie Weaver, Ph.D. 
    Institution: Purdue University 
    The research project is testing the hypothesis that vaccinium berry extracts reduce bone loss by estrogen deficiency at menopause. This supplement will compare the effectiveness of berry extracts to prevent bone loss induced by "male androgen deficiency" in mice with their effects on preventing bone loss induced by estrogen deficiency. They also will determine whether the transcription factor, Nrf2, and/or drug metabolizing enzymes are required for protection against androgen loss.
  • Hypothalamic inflammation in the initiation of cancer cachexia 
    Principal Investigator: Daniel L. Marks, M.D., Ph.D. 
    Institution: Oregon Health and Science University 
  • The role of CHD5 in chromatin-mediated regulation of neural stem cells and glioma 
    Principal Investigator: Alea A. Mills, Ph.D. 
    Institution: Cold Spring Harbor Laboratory 
    The project is trying to decipher genetic/epigenetic mechanisms that regulate the fine balance between tissue homeostasis and glioma. Glioma is a brain malignancy that is ~1.5 times more prevalent in men than women. With the help of glioma mouse model, this supplement will examine how sexual dimorphism affects the machinery that packages DNA to control the behavior of brain cells, and will elucidate how defects in this process can lead to brain cancer.
  • Single cell analysis strategy for monitoring drug responses of tumors 
    Principal Investigator: Qiang Tian, Ph.D., M.D., B.S. 
    Institution: Institute of Systems Biology 
    The project is performing next-generation sequencing of short reads and mapping to a reference genome using a cohort of 40 patients. Their preliminary data suggested previously undetected sex biases in depth of coverage, which may lead to inconsistent results in the ability to identify copy number variants and single nucleotide variants. The supplement will help them develop methods and tools to correct sex bias in genome sequencing, utilizing existing datasets from males and females.

Application of two animal models in pursuit of myopia control 
Principal Investigator: Christine Wildsoet, O.D., Ph.D. 
Institution: University of California at Berkeley 
The project is trying to improve treatment efficacy for myopia (short-sightedness) by developing a multi-pronged approach (molecular biology, optical imaging and function testing). Sex bias is observed in myopia where females develop the disease earlier and tend to progress to higher levels than males. This supplement will determine the sex hormone-related influences on ocular growth and myopia, including the effects of systemic sex hormones on susceptibility to myopia inducing optical defocus stimuli.

  • Disruption of the clock O-GlcNAc axis in diabetic cardiomyopahty 
    Principal Investigator: John C Chatham, Ph.D., B.S. 
    Institution: University of Alabama at Birmingham 
    The project is trying to understand whether the posttranslational modification, O-GlcNAcylation, contributes to diabetes-induced alterations of the cardiomyocyte circadian clock, leading to cardiac dysfunction. Their preliminary data indicated that overall O-GlcNAc levels were higher in the hearts of female than male mice. They have also shown that the cardiomyocyte circadian clock directly influences total cardiac O-GlcNAc levels. In the supplement, they will add ~400 female mice to examine sexual bias on O-GlcNAc levels, as well as circadian-dependent protein synthesis and damage. 
  • Directed culturing of pneumocystis using metatranscriptomics 
    Principal Investigator: Melanie T. Cushion, Ph.D. 
    Institution: University of Cincinnati 
    With the help of metatranscriptomics, the project is trying to identify enzymes, transporters, and other metabolic genes that are highly expressed in the growing populations of Pneumocystis and in the lung biome because no species of Pneumocystis can be grown outside the mammalian lung. In the supplement, they will add female mice to identify differences in host immune responses to the Pneumocystis and the corticosteroids used to debilitate the immune system that result in more severe infection in females. 
  • Functional hierarchy of remnant lipoprotein receptors 
    Principal Investigator: Sergio Fazio, M.D., Ph.D. 
    Institution: Oregon Health and Science University 
    The project focuses on the role of macrophages in the pathogenesis of atherosclerosis (more prevalent in males than females of reproductive age). They will identify the molecular mechanisms for the effects of two proteins, Apolipoprotein E (ApoE) and Low density lipoprotein Receptor-related Protein 1 (LRP1), responsible for cholesterol trafficking, regulation of inflammation, cell viability, and disposition of cell debris. The supplement will focus on exploring effects of male and female macrophages and aortic wall cellularity in relation to ApoE and LRP1 expression. 
  • Mitochondrial quality control in cardioprotection 
    Principal Investigator: Roberta A. Gottlieb, M.D. 
    Institution: Cedars-Sinai Medical Center 
    The project is trying to dissect the molecular mechanisms behind impaired autophagy, a key feature of aging and metabolic syndrome. Impaired autophagy affects inflammation, cardio-protection, and postinfection remodeling. The supplement will determine whether sex differences affect autophagy and cardio-protection in young vs. aged mice, and in mice on normal chow vs. high-fat diet. 
  • Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension 
    Principal Investigator: Iris Z. Jaffe, M.D., Ph.D. 
    Institution: Tufts Medical Center 
    The project is exploring novel mechanisms for the rise in blood pressure (BP) with aging in order to identify more effective therapies to specifically treat hypertension in senior citizens. This supplement will study sexual dimorphism by adding female mice to their ongoing studies in male mice and will compare the data to explore novel vascular mechanisms of BP regulation with aging.
  • Regulations of myoendothelial function by signaling microdomains in hypertension 
    Principal Investigator: Mark T. Nelson, Ph.D., B.A. 
    Institution: University of Vermont 
    The project is trying to elucidate the signaling networks involved in mediating endothelial dependent vascular dysfunction, a major factor in many cardiovascular disease processes. They have recently shown that there is a fundamental difference in transient receptor potential vanilloid 4 activity (i.e., channel open probability and agonist sensitivity) between small arteries in the periphery (mesenteric) and cerebral arteries when derived from male mice. The supplement will add female mice to provide important insights into aspects of vascular function and dysfunction that potentially differ between males and females. 
  • Development of Prognostic Platelet RNA Biomarkers to Tailor Antiplatelet Therapy 
    Principal Investigator: Deepak Voora, M.D. 
    Institution: Duke University 
    The project has proposed to develop whole blood RNA biomarkers that can identify individuals at high risk for acute coronary syndrome (ACS) on aspirin, the most commonly used antiplatelet agent. It is well known that low-dose aspirin is ineffective in preventing myocardial infarction in women compared to men. The supplement will use system pharmacology to identify sex-specific differences in the platelet transcriptomes, proteins, pathways, and potential novel pharmacologic targets with respect to their response to low-dose aspirin.
  • Tailored inhibitory control training to reverse EA-linked deficits in mid-life 
    Principal Investigator: Elliot T. Berkman, M.A., B.S., B.A., M.A., Ph.D. 
    Institution: University of Oregon 
    The project is testing the efficacy of a tailored inhibitory control (IC) training intervention to improve inhibitory control, alter its neural systems, and reduce health-risking behaviors (like drug, alcohol, and tobacco use, and unhealthy eating) in a sample of mid-life adults who experienced early adversity. The supplement will support 30 additional participants, allowing sufficient power to determine the nature and magnitude of gender differences in neural activation at baseline and in response to IC intervention. 
  • Cell Autonomous and Non-Autonomous Mechanisms of Aging 
    Principal Investigator: Paul D. Robbins, B.A., Ph.D. 
    Institution: Scripps Research Institute 
    The project is testing the notion that stochastic cellular damage, in particular, DNA damage promotes aging through a predominantly cell autonomous mechanism by triggering programmed cell death or senescence. Their preliminary data showed the evidence of age-related events that vary between male and female mice. In the supplement, they will increase the power by adding more mice to determine whether the sex-specific differences are significant in factors that drive aging or in the response to novel drugs they are developing to extend health span. 
  • Role of lipid droplets in neurovascular inflammation 
    Principal Investigator: John C. Rutledge, M.D. 
    Institution: University of California at Davis 
    The project is studying human brain microvascular endothelium in culture and in male mouse models to examine the impact of a high blood lipid and lipoprotein environment on the neuro-vasculature and on cognitive impairment. There is virtually no evidence of the sex specificity and gender regulation in this area of study. The supplement will add animals and cells of the opposite sex to allow sex-based comparisons between data obtained by the parent grant and by the supplement. 
  • Frailty and risk prediction in older adults considering kidney transplantation 
    Principal Investigator: Dorry L. Segev, M.D., Ph.D. 
    Institution: Johns Hopkins University 
    The project is a prospective cohort study of older adults (>55 years) with end stage renal disease (ESRD) to obtain novel metrics and outcomes to streamline the referral guidelines of older adults for kidney transplant. The supplement will explore sex as an effect modifier of frailty/inflammation on ESRD outcomes to test whether these novel predictors differentially affect women. If effect modification exists, they will develop a female-specific decision process model. 
  • Quantifying changes in neural stem cell lineages in the aging niche 
    Principal Investigator: Sally Temple, Ph.D., B.A. 
    Institution: Regenerative Research Foundation 
    The project is trying to understand how changes in progenitor behavior might contribute to diseases of aging such as Alzheimer by identifying cellular and molecular targets to alleviate aging-related neurodegenerative changes in the adult stem cell niche. This supplement will characterize sex differences in neural stem cell behavior and stem cell niche structure by adding female mice and cells to the parent study which only examined these parameters in male mice/cells.
  • The Impact of HPA axis dysregulation on the interoceptive effects of alcohol 
    Principal Investigator: Joyce Besheer, Ph.D. 
    Institution: University of North Carolina at Chapel Hill 
    The project is focused on examining the effects of chronic stress hormone exposure on sensitivity to the interoceptive effects of alcohol and alcohol drinking, and the functional consequence of neuroadaptations in nucleus accumbens in male rats. The supplement will add female rats to increase our understanding of sex differences in relation to stress-induced changes to the interoceptive effects of alcohol and alcohol self-administration. 
  • Role of Neuropeptides in Stress-Induced Escalation of Alcohol Drinking 
    Principal Investigator: Nicholas W. Gilpin, Ph.D. 
    Institution: LSU Health Sciences Center 
    The project uses animal models to explore the neurobiological basis for alcohol abuse in individuals with post-traumatic stress disorder (PTSD), with the ultimate goal of tailoring the effective therapeutic strategies to reduce alcohol drinking in humans with PTSD. There is a lack of research directly investigating the neurobiology of traumatic stress-induced escalation of alcohol use. The supplement will add female animals to examine sex differences in traumatic stress reactivity and stress-induced escalation of alcohol drinking.
  • Etiology and Treatment of Alcohol Dependence 
    Principal Investigator: Victor M. Hesselbrock, Ph.D., M.S.S.W., B.A. 
    Institution: University of Connecticut Health Center 
    The project is evaluating the connections of the candidate genes and brain dysfunction to both body mass/adiposity and likely indicators of alcoholism risk. Their preliminary data using dataset of two cohorts of 123 and 220 subjects revealed that body mass index was positively correlated with the substance use disorder associated GABRA2 genotype in females but not in males. The supplement will add 100 adolescent males to their female only study to understand sex differences in the connection between impulsivity and obesity/alcohol use. 
  • Modeling the influence of sex on natural killer cell networks 
    Principal Investigator: Catherine A. Blish, M.D., Ph.D. 
    Institution: Stanford University 
    The project is analyzing how the human natural killer (NK) cells recognize and respond to the immune defense against HIV, CMV and influenza to improve an antiviral response in a vaccine or therapeutic setting. Their preliminary data showed significant differences between males and females in the NK cell repertoire and responsiveness of NK cells. The supplement will add females to explore the influence of sex on the diversity and dynamics of the NK cell repertoire. 
  • Modulation of innate immunity, microbiome and HIV transmission by Depo-Provera 
    Principal Investigator: Theresa Li-yun Chang, Ph.D. 
    Institution: Rutgers, The State University of New Jersey 
    The project is studying the association between injectable contraceptives and microbiomes (cervicovaginal and colonic) for increased simian/human immunodeficiency virus (SHIV) transmission and pathogenesis in the non-human primate (NHP) model of HIV infection. Their preliminary data showed that SHIV infected females have increased innate immune responses, differences in microbiome and a significant decrease in survival. The supplement will study the sexual dimorphism by understanding the cross-talk between the rectal mucosal microbiome and local innate immune environment in male and female NHPs (rhesus macaques). 
  • Mechanisms Underlying Persistent Lentivirus Replication in Follicular T Cells 
    Principal Investigator: Elizabeth Connick, M.D. 
    Institution: University of Colorado Denver 
    The project is trying to identify factors within the follicular milieu of lymphoid tissues that promote HIV-1 replication in T follicular helper cells (TFH), the major virus-producing cells in vivo. The supplement will determine the underlying mechanisms of sex differences in plasma viral loads in HIV-1 infection because their preliminary data showed that T follicular regulatory cells in women express higher levels of CTLA-4 than men, resulting in enhanced suppression of HIV-1 replication within TFH.
  • Center for Research in Diagnostics and Discovery 
    Principal Investigator: Ian W. Lipkin, M.D. 
    Institution: Columbia University 
    The project is dealing with the global public health threat of emerging virus infections because of the difficulties in responding to contain or treat previously unknown or uncharacterized pathogens. Their recent publication in Science showed that infected male mice exhibited distinct disease phenotypes, indicating genetic preference to Ebola infection. The supplement will add female mice to address sex bias in the pathophysiological and immunological outcomes to Ebola infection.
  • Translational Studies of GAA Deficiency in Bioengineered Human Muscle 
    Principal Investigator: Nenad Bursac, Ph.D. 
    Institution: Duke University 
    The project will carry out in vitro and in vivo studies to screen and validate alternative and adjuvant drug, and gene therapies for Glycogen storage disease type II (Pompe disease), a fatal degenerative disease caused by the deficiency of acid-alpha glucosidase (GAA) or acid maltase. The goal of the supplement is to improve the sex-dependent efficacy of gene therapy in Pompe disease, using mouse model and in vitro human engineered muscle model to overcome sex-dependent differences in the efficacy of treatment.
  • Role of Notch Signaling in Osteocytes 
    Principal Investigator: Ernesto Canalis, M.D. 
    Institution: University of Connecticut Health Center 
    The project is trying to understand the functional role of Notch is osteocytes, using in vitro and in vivo mouse models (wild type and genetically engineered) expressing Notch in the osteocyte. Notch plays a critical role in cell differentiation and its expression in immature osteoblasts causes osteopenia (decreased bone density). The supplement will study sex dependent bias in the osteocyte cell pool, gene expression and determine whether sex differences in the osteocyte cell pool are Notch-dependent. 
  • Developing an Alopecia Areata Disease Activity Index (ALADIN) 
    Principal Investigator: Angela M. Christiano, Ph.D. 
    Institution: Columbia University 
    The project is developing an instrument, Alopecia Areata Disease Activity Index (ALADIN), to determine clinically relevant endpoints for Alopecia Areata (AA), one of the most common autoimmune diseases affecting more females than males. The supplement will study sexual dimorphism by increasing the number of male and female samples and applying systems-biological approaches to generate genetic regulatory models for disease initiation and progression in AA. 
  • Bone Robustness as a Biomarker of Skeletal Aging and Fragility 
    Principal Investigator: Karl J. Jepsen, Ph.D. 
    Institution: University of Michigan 
    The project is developing predictive biomarkers for fracture risk earlier in life and for providing insight into the fragility-related biological activities. Since, female bones have greater resoptive activity than men, the supplement will test how in situ biological processes (osteoclastic resorption) contribute to sex-specific differences in the age-related decline of strength of the proximal femur bone.
  • Sclerostin Antibody Therapy for Treatment of Osteogenesis Imperfecta 
    Principal Investigator: Kenneth Kozloff, Ph.D. 
    Institution: University of Michigan 
    The project is investigating the mechanisms of sclerostin antibody therapy on bone cell activity, mass, and material quality in a mouse model of osteogenesis imperfecta (OI) to find out whether this therapy will decrease bone fragility. This supplement will add female mice to the parent studies of male mice only, to study sex differences by directly comparing the two sexes in the actions and sustainability of anabolic effects of sclerostin antibody as a potential new therapeutic drug for treating OI. 
  • Determination of the Mechanisms by which IGFBP-2 Stimulates Bone Remodeling 
    Principal Investigator: Clifford J. Rosen, M.D. 
    Institution: Main Medical Center Research Institute 
    The project is interrogating the role of insulin like growth factor binding protein-2 (IGFBP-2) on osteoblasts and the impacts of loss of IGFBP-2 in osteoblasts on bone metabolism. This supplement will add female mice to identify sex-specific differences in bone cells and their response to sex steroids through in vitro and in vivo studies to elucidate novel targets for the treatment of osteoporosis. 
  • Central Mechanisms involved in the interactions between muscle pain and exercise 
    Principal Investigator: Kathleen A. Sluka, Ph.D. 
    Institution: University of Iowa 
    The project is investigating underlying mechanisms in a paradox that a single bout of unaccustomed exercise increases pain (sedentary model) while repeated exercise is analgesic (exercise-induced pain model). Preliminary data revealed that the exercise-induced pain model showed robust sex differences in sedentary animals. The supplement will add both male and female mice to examine the role of gonadal hormones and determine sex differences in development of widespread hyperalgesia.

A Multi-Scale Modeling Construct of Knee Mechanics following ACL Reconstruction 
Principal Investigator: Yasin U. Dhaher, Ph.D. 
Institution: Rehabilitation Institute of Chicago 
The project is trying to develop a multi-scale model of a common surgical intervention to identify the differential and combined effects of the surgical and musculoskeletal factors that may contribute to the aberrant post-surgical cartilage loading. The supplement, by examining the effect of hormones on post-surgical degradation of the cartilage in the female population, will provide insights into the etiology of the gender bias in the post-surgical development of osteoarthritis.

  • Spinal Circuits and the Musculoskeletal System 
    Principal Investigator: Arthur W. English, Ph.D. 
    Institution: Emory University 
    The project is doing a detailed analysis of peripheral nerve injury in a rat model with a focus on exercise and other therapeutic approaches to promote functional recovery. In the supplement, they will add male rats (neve injury is significantly higher in males than females) to examine sex differences at the level of spinal cord plasticity, axon regeneration, response to exercised therapies, and functional recovery.
  • Adverse Outcomes of Assisted Reproductive Technologies: Genetics or Epigenetics? 
    Principal Investigator: Margareta Pisarska, M.D.
    Institution: Cedars-Sinai Medical Center
    The project will identify genomic and epigenomic variants associated with Assisted Reproductive Technologies (ART), which has been linked to adverse pregnancy outcomes. Their preliminary data, at this very early stage, showed significant sex differences in gene expression, including genes that were not on the sex chromosomes. The supplement will increase sample size and power, and will disentangle the contributions of underlying infertility vs. the effects of ART on fetal origin of adult diseases.
  • Protein Modifications and Unfolded Protein Response in Diabetic Embryopathy 
    Principal Investigator: Zhiyong Zhao, Ph.D.
    Institution: University of Maryland, Baltimore
    The project is determining underlying mechanisms of diabetic embryopathy, especially focusing on increased post-translational modification by O-GlcNAcylation, which through various pathways leads to structural birth defects. This supplement will determine sexual differences in the susceptibility to embryonic malformations to maternal hyperglycemic insult as well as whether there are sexual dimorphism in response to interventions in diabetic pregnancies.
  • Sex Differences in Adolescent Exposure to Morphine on Reward Related Behaviors in Subsequent Offspring 
    Principal Investigator: Elizabeth M. Byrnes, Ph.D. 
    Institution: Tufts University 
    The project is examining self-administration patterns in the offspring of females exposed to morphine during adolescent development. The researchers have observed transgenerational effects, suggesting that offspring of mother's exposed to morphine during adolescence demonstrate a shift in addiction-like behavioral phenotype. This supplement will study sexual differences by investigating the effects of opiate exposure on adolescent males. 
  • Utilizing Interaction to Identify Novel Genetic Factors for Nicotine Dependence 
    Principal Investigator: Dana Hancock, Ph.D. 
    Institution: Research Triangle Institute 
    The project has an overarching goal to discover novel genetic variant associations with nicotine dependence (ND) by leveraging gene-gene interactions with established risk variants from nicotinic acetylcholine receptor genes discovered in previously funded GWAS studies. This supplement will use same sample cohort and statistical methodology to study sex differences by identifying new genes associated with ND, one of the strongest predictors of failing to quit cigarette smoking. 
  • Behavioral and Epigenetic Mechanisms in Extinction of Cocaine-Induced Memories 
    Principal Investigator: Matthew Lattal, Ph.D. 
    Institution: Oregon Health and Science University 
    The project is evaluating the role of epigenetics in causing the persistent elimination of drug-seeking behavior. Their preliminary data showed that epigenetic mechanisms of gene regulation are critical for the modulation of extinction. The supplement will add females to examine whether males and females are equally sensitive to pharmacological manipulations of epigenetic targets, coupled with viral manipulations of downstream gene targets. 
  • Synaptic Actin Dynamics and the Selective Vulnerability of Drug-Associated Memory 
    Principal Investigator: Courtney Miller, B.S., M.S., Ph.D. 
    Institution: Scripps University 
    The project is investigating therapeutic potential of novel small molecules that specifically "erase" drug-specific memories in male rodents. They have identified the synaptic actin cytoskeleton as a biological target for the selective disruption of the drug associations capable of triggering relapse. The supplement will extend these studies to explore the effects of small molecule modulators on drug-associated memories in female animals. 
  • Modulation of norepinephrine by cannabinoids 
    Principal Investigator: Elisabeth Van Bockstaele, Ph.D. 
    Institution: Drexel University 
    The project combines neuroanatomy to define circuitry within the brain with functional behavioral and neurochemical outcomes in the study of stress and its perturbation with opiates. Their recent work showed that females exhibited different stress-induced activation patterns. The supplement will perform mechanistic studies to explain sex difference in the opiate system and its nexus with norepinephrine and stress-related hormone. 
  • Sex Differences in the Cannabinoid Regulation of Energy Homeostasis 
    Principal Investigator: Edward J. Wagner, Ph.D., B.S. 
    Institution: Western University of Health Sciences 
    The project is studying the effects of gonadal hormones on cannabinoid regulation of energy homeostasis. They have noticed (i) cannabinoid-induced hyperphagia is sexually disparate, with males being more responsive than females, (ii) estrogen diminished sensitivity to cannabinoid effects in females, and (iii) androgens increased sensitivity in males. The supplement will study sex bias in behavior and hormonal modulation to inform potential sex differences that might be expected in the use of cannabinoid-based therapeutics for treating disturbances of energy homeostasis.

Computational characterization of language use in autism spectrum disorder 
Principal Investigator: Jan P. van Santen, Ph.D. 
Institution: Oregon Health and Science University 
The goal of the project is to develop and validate new Natural Language Processing (NLP) based methods that automatically measure Autism Spectrum Disorders (ASD)-specific features of atypical language use, including decreased social reciprocity and increased repetitive speech behaviors. The female clinical presentation of ASD is not well understood because it occurs more frequently in males, with a 4:1 ratio. The supplement will increase sample size of females with ASD to characterize clinical presentations and compare data with that of males.

  • Mass Spectrometry Tools in Pursuit of Salivary Biomarkers of Sjögrens Syndrome 
    Principal Investigator: Steven Hall, Ph.D. 
    Institution: University of California, San Francisco 
    The project is trying to discover candidate biomarkers of primary Sjögren's Syndrome (pSS) in human saliva by utilizing mass spectrometry (MS)-based approaches. Since, pSS affects primarily women (9:1), all saliva samples are from female donors through the Sögren's Syndrome International Collaborative Clinical Alliance (SICCA) biorepository. The supplement will include the discovery and verification of candidate biomarkers in male saliva samples, who were part of SICCA cohort. 
  • Gender differences in stress-induced pain transition after surgery 
    Principal Investigator: Feng Tao, M.D., Ph.D. 
    Institution: Texas A&M University Health Science Center 
    The goal of the project is to develop a new animal model to study pain transition (acute to chronic) and provide critical evidence to characterize the pain transition model. They recently observed that female mice showed longer postsurgical pain after stress treatment compared to that in male mice. The supplemental will add female mice to investigate sex differences in psychological stress-induced development of chronic postsurgical pain.
  • Innate Immunity End Experimental Crohn's Disease 
    Principal Investigator: Fabio Cominelli, M.D., Ph.D. 
    Institution: Case Western University 
    The project is challenging the traditional paradigm of Crohn disease (CD) (overly aggressive adaptive immune response against luminal antigens) and examining whether the disease results from an abnormality in innate immune responses to luminal antigens. The etiology of the disease is unknown but sex disparity has been reported - increased incidence and severity in females. The supplement will increase samples size and conduct new comparative analyses to understand sex differences in the etiology and pathogenesis of the disease. 
  • Role of ACSL5 in intestinal and liver Triacylglycerol Metabolism 
    Principal Investigator: Andrew Greenberg, M.D. 
    Institution: Tufts University 
    The project is investigating the role of acyl-CoA synthetases (ACSL) on lipid metabolism and its possible role in obesity. Their preliminary data showed that female but not male mice when fed low fat and low sucrose diet exhibited improvements in serum lipids, obesity and blood glucose levels. In the supplement they will add female mice to investigate the role of ACSL5 in obesity, diabetes and fatty liver and the molecular mechanisms of sex differences, using wild type and gene knock-out mice. 
  • Expression and iron-independent functions of Siderophores in urinary tract infections 
    Principal Investigator: Jeffrey P. Henderson, M.D., Ph.D. 
    Institution: Washington University in St. Louis 
    The project is gaining new insights into the role of siderophores (a chemically diverse family of small molecules defined by their ability to bind ferric iron for microbial use) in the pathogenesis of urinary tract infections, and identify new diagnostic and therapeutic strategies for this illness. Recently, they have identified an interaction between a virulence associated uropathogenic E. coli (UPEC) siderophore and host-derived copper ions. The supplement will add males to their "female-only" studies to conduct new comparative analyses to better define the sex differences associated urinary metabolites. 
  • Molecular and Epidemiologic Basis of UTI in Women 
    Principal Investigator: Scott Hultgren, Ph.D.
    Institution: Washington University in St. Louis
    The project is developing a preclinical model of urinary tract infections employing direct bladder inoculation of E. coli for determination of sex-specific differences. Their preliminary data showed increased male susceptibility to chronic cystitis, pyelonephritis and renal abscess formation which was abrogated with castration. The supplement will use systems biology approaches to define the sex-specific early host responses to E. coliand to model sex influences on treatment response. 
  • Mapping Hypothalamic Neurocircuits Controlling Physical Activity 
    Principal Investigator: Holly A. Ingraham, Ph.D. 
    Institution: University of California, San Francisco 
    The project is investigating hormonal regulation of neural circuits controlling physical activity to target sedentary behavior in post-menopausal women. Recently, they observed a sexually dimorphic neuronal cluster in the hypothalamus that controls physical activity in females. Since only a male transgenic mouse model "ThermoMice" exists, the supplement will generate a new "brown adipose tissue reporter" mouse model that can be leveraged to monitor hormonal regulation of brown adipose tissue thermogenesis in vivo and to compare the data with that of male mice. 
  • Center for Neurovisceral Sciences and Women's Health 
    Principal Investigator: Emeran Mayer, M.D. 
    Institution: University of California, Los Angeles 
    The project is studying the sex differences in Irritable bowel syndrome (IBS) with an emphasis on biologic systems related to stress to develop better treatment options. IBS is a common stress responsive disorder with limited treatment choices affecting predominantly females. Their recent data showed that changes in the fecal microbiota act beyond the local gut effects (e.g. intestinal permeability, immune function) and can also affect CNS function and behavior. The supplement will add fecal metabolomics to the existing IBS endophenotyping approach and will also examine how sex differences interact with the biological microbiota. 
  • Genetic epidemiology of rare and regulatory variants for metabolic traits 
    Principal Investigator: Karen Mohlke, Ph.D. 
    Institution: University of North Carolina at Chapel Hill 
    The project is identifying novel genetic variants that are responsible for variability in metabolic traits and risk to the related diseases (e.g., diabetes, obesity, and the metabolic syndrome) in the all-male METabolic Syndrome In Men (METSIM) study. The data suggests that about 40% of the genetic loci have significantly stronger effects in women than in men. The supplement will add opposite sex (females) to allow sex-based comparisons in their genome-wide analysis of genetic variants, gene expression in subcutaneous adipose tissue, and metabolic traits, using results from the all-female TwinsUK study. 
  • Regeneration of the Lower Urinary Tract in Nonhuman Primates 
    Principal Investigator: James Koudy Williams, DVM 
    Institution: Wake Forest University Health Sciences 
    The goal of the project is to examine the mechanisms and long-term efficacy of skeletal muscle precursor cell therapy on structural and functional changes of the urinary sphincter complex in a female nonhuman primate model of intrinsic urinary sphincter muscle deficiency (ISD). ISD is commonly associated with nerve damage during prostatectomies in men and during child birth in women. The supplement will add male monkeys to study sex differences in skeletal muscle precursor cell therapy.
  • Correcting for Population Structure in Gene-by-Environment Interaction Studies 
    Principal Investigator: Eleazar Eskin, Ph.D. 
    Institution: University of California, Los Angeles 
    The project is developing a set of methods that could detect gene-by-environment (GxE) interactions consistently even when the individuals in the study are related. Genome-wide association studies (GWAS), which does not discriminate between males and females, have been frequently used to identify numerous genetic loci associated with complex human traits. However, recent studies have observed sex differences in effect sizes at a number of genetic loci. The supplement will develop statistical methods to identify sex-specific interactions in genetic studies. 
  • Building the Foundation of Epigenomics Roadmaps 
    Principal Investigator: Zhaoyu Li, M.D. 
    Institution: Mayo Clinic, Jacksonville 
    The project is trying to develop a novel algorithm to map normal epigemomic regulation at single nucleosome position across cell types and developmental stages, and to translate their data to understand how epigenetic misregulation may contribute to disease development. With the help of normal human liver biospecimens and human embryonic stem cells, the supplement will study how common and sexually dimorphic regions of nucleosome positioning might contribute to the male/female differences in liver cancer progression. 
  • Nitrate dependent protection against chlorine gas toxicity-role of chlorinated lipids 
    Principal Investigator: Rakesh Patel, Ph.D. 
    Institution: University of Alabama at Birmingham 
    The project is evaluating the efficacy of nitrate as a post exposure therapy that can be used in mass casualty to attenuate chlorine (Cl2) gas induced toxicity. Cl2 gas mediated injury involves a direct toxicity (during the exposure) and a robust post exposure toxicity (over hours/days to the airways, pulmonary, and systemic vasculature). Their pilot data showed that female mice were significantly more sensitive to Cl2 gas-induced injury and were least protective by nitrate therapy compared to males. The supplement will address the sex differences in Cl2 gas-induced mortality and efficacy for nitrate-based therapy.
  • Form and Function of our Janus faced genome 
    Principal Investigator: Jayakrishna Ambati, M.D. 
    Institution: University of Kentucky 
    The project is focused on defining the form and function of their recently identified new class of genetic material termed "endogenous cDNA" (ecDNA). This unexplored genome may be a rich source of novel biologic function. Their preliminary data suggested that substrates for endogenous cDNA production were specifically elevated in females. In the supplement, they will compare males and females to determine sex-specific differences in ecDNA biology. They will also assess whether sex-specific differences in ecDNA correlate with human disease that is more prevalent in women. 
  • Cellular Protein Involved in Trafficking of HIV-1 
    Principal Investigator: Carol A. Carter, Ph.D. 
    Institution: Stony Brook University 
    The project is investigating the role of calcium signaling machinery in HIV-1 production and its relationship to endocytic sorting complexes required for transport (ESCRT) machinery. They have discovered that treatment of infected cells with a calcium channel blocker induces changes in the viral particle that are very similar to changes resulting from mutations in ESCRT factor-binding determinants. The goal of this proposal is to investigate properties of HIV-1 that may facilitate evasion of immune and drug surveillance during virus replication, thereby facilitating gender-biased transmission and preventing effective treatment.
  • The evolution and spread of virulent infectious disease 
    Principal Investigator: Wayne Potts, Ph.D. 
    Institution: University of Utah 
    The project is studying the relationship of host genetic diversity to transmissibility, replication, and evolution of viral virulence. They have recently shown substantial host sex differences in virulence due to Friend virus infections that corresponds with differences in susceptibility and transmission. The supplement will add the key feature "host sex" as an experimental factor to understand the influence of sex on evolution of viral virulence.
  • Face processing systems in schizophrenia spectrum disorders 
    Principal Investigator: Yue Chen, Ph.D. 
    Institution: McLean Hospital 
    The project is studying facial processing system in schizophrenia, using psychophysical and neuroimaging studies. Although sex differences in the onset and recovery of schizophrenia are well-documented, the underlying brain mechanism is not well understood. The supplement will examine sexual dimorphism as a source of variance differentiating brain structure and function in schizophrenia and healthy individuals.
  • Stressor Controllability: The Role of the mPFC in Producing Resiliency 
    Principal Investigator: Steven F. Maier, Ph.D., A.B. 
    Institution: University of Colorado 
    The project is trying to understand how behavioral modifications regulate brain circuits and the generation of stress-related disorders. With the help of male rats, they have shown that experiences with controllable/escapable stressors make rats resistant to future stressors. Since, women have a higher risk for stress-related psychopathology, the supplement will use female rats to determine if stressor controllability effects are present in females and whether it uses the same circuits as established in males.
  • REM Sleep and Memory 
    Principal Investigator: Gina R. Poe, Ph.D. 
    Institution: University of Michigan 
    The project investigates the role of locus coeruleus (LC) activity during sleep in the disturbances of reversal learning that may be relevant to excessive encoding of fearful memories in PTSD. PTSD is more prevalent in women than in men, and that gonadal hormones may contribute to sex differences in fear extinction and PTSD. The supplement will add female rats to examine the effects of sex hormones on consolidation of fear and extinction memories via activation of LC noradrenergic neurons during sleep.
  • Kynurenic Acid and Cognitive Abnormalities in Schizophrenia 
    Principal Investigator: Robert Schwarcz, Ph.D. 
    Institution: University of Maryland 
    The project is looking at the role of kynurenic acid (KYNA), a neuroactive compound that is elevated in the brain of individuals with schizophrenia (SZ) in cognition, and examining inhibition of KYNA formation as a novel strategy to overcome cognitive dysfunction. In the supplement, they will add female animals to provide new insights into the sexually-dimorphic role of the tryptophan metabolite KYNA, and compare the data with that of the parent grant, which is using male animals only.
  • Neurophysiological markers of HAND and the impact of aging: Evidence from MEG 
    Principal Investigator: Tony W. Wilson, Ph.D., B.S. 
    Institution: University of Nebraska Medical Center 
    The parent study is examining the neurophysiological basis and progression of HIV-associated neurocognitive disorders, using magnetoencephalography, and determine how chronic HIV-infection modulates the effects of aging on cognitive performance and brain physiology. The supplement will enroll 60 females (30 HIV-infected and 30 matched controls) to evaluate sex differences in the way aging and HIV impact cognitive performance and brain function in female compared to male patients.
  • Brain endothelial cell function under adenosine receptor signaling directive 
    Principal Investigator: Margaret S. Bynoe, Ph.D., B.S. 
    Institution: Cornell University 
    The project aims to investigate adenosine receptor (AR) modulation of the blood brain barrier (BBB) and its potential as a drug delivery tool. They have recently shown that signaling via A2A AR regulates BBB permeability. The parent application is using male animals only and very little is known in females. In the supplement, they will add female mice to understand the physiology of BBB in female mice and compare the data to understand the sexual bias.
  • The Role of ASICs in Migraine Pathophysiology 
    Principal Investigator: Gregory O. Dussor B.S., Ph.D. 
    Institution: University of Texas Dallas 
    The project is studying targets on dural afferents that lead to afferent pain signaling. They recently discovered that dural afferents are extremely sensitive to decrease in extracellular pH. In the supplement they will add female rats to study sex differences in the sensitivity of the dural afferent system to pH under normal conditions and differences in the sensitization of this system between sexes that would inform development of new therapeutics for migraine between sexes.
  • Beta Endorphin Neurons and the Control of Homeostasis 
    Principal Investigator: Martin Jeffrey Kelly, Ph.D., B.S. 
    Institution: Oregon Health and Science University 
    The project is elucidating the mechanism by which 17 β-estradiol (E2) signals in hypothalamic neurons to protect against insulin resistance. Women show increased risk of insulin resistance, central adiposity, and cardiovascular disease with the onset of menopause. The supplement will incorporate male subjects to understand the sex steroid-specific signaling in hypothalamic neurons that protects against the development of insulin resistance in diet induced obesity.
  • Basal ganglia and sleep related motor disorders 
    Principal Investigator: Yuan-Yang Lai, Ph.D. 
    Institution: Sepulveda Research Corporation 
    The project is developing animal models of Restless Legs Syndrome (RLS) and Periodic Leg Movements (PLM) of sleep, which affect 10% of the population and 32% of iron deficient anemia patients. They have shown that PLM can be reversed in male rats with iron replacement. However, RLS is female predominant disorder. In the supplement, they will use both male and female rats to determine whether sex difference play a role in the regulation of sleep and motor activity.
  • Nociceptor mechanisms in the transition from acute to chronic pain 
    Principal Investigator: Jon David Levine, M.D., Ph.D. 
    Institution: University of California San Francisco 
    The project is focused on the understanding of acute-to-chronic pain at the level of the peripheral nociceptor, and potential prevention and reversal of such enhanced pain states. They have recently shown that neuroplasticity in primed nociceptors, related to the transition from acute to chronic pain, can be prevented by the peripheral administration of a protein translation inhibitor. In the supplement, they will study sexual dimorphism of the critically important clinical phenomenon of transition from acute to chronic pain.
  • Brain injury due to soccer heading and opportunities for its mitigation 
    Principal Investigator: Michael L. Lipton, M.D., M.S., B.A., Ph.D. 
    Institution: Albert Einstein College of Medicine 
    The project is studying traumatic brain injury (TBI) in soccer players who head the ball by examining structural (traumatic axonal injury (TAI)) and functional (cognition and post-concussion symptoms (PCS)) changes. Their preliminary studies showed that those who head more than 1,000 times per year are at increased risk for TBI. The supplement will recruit 75 amateur soccer players and 75 matching noncontact sport controls to study sex bias in TBI. They will also study the role of sex hormones by longitudinally tracking PCS and cognition throughout the menstrual cycle of female participants.
  • Epigenome Interactions in Complex Neurogenetic Disorders 
    Principal Investigator: Margaret Elizabeth Ross, M.D. 
    Institution: Weill Medical College of Cornell University 
    The project is studying epigenetic modifications in the setting of prenatal supplementation that might impact a recognizable pattern of gene expression to either favor or impair neurulation that can be predicted based on individual genotype. Their preliminary data found striking differences between males and females in the epigenetic landscape and responses to dietary folic acid supplementation. The supplement will expand the existing project by examining the sex/gender differences in physiological and disease processes.
  • Neuroprotection in the Aging Female Brain 
    Principal Investigator: Farida Sohrabji, Ph.D., M.S., B.A. 
    Institution: Texas A&M University Health Science Center 
    The project is exploring the underlying mechanisms of estrogen's neuroprotective role following ischemic stroke in mature females but increased tissue damage in older females. They have shown the interaction of estrogen with insulin-like growth factor-1 (IGF-1), which undergoes an age-related decline. The supplement will add male rats to examine the sex-related changes in IGF-1 binding proteins for the differential susceptibility to stroke between males and females, hopefully leading to a new therapeutic approach for stroke recovery either by inhibiting IGF-1 proteins or specific hormone receptors.
  • Regulatory Control of Glutamate-Induced Superoxide Production 
    Principal Investigator: Raymond A. Swanson, M.D. 
    Institution: Northern California Institute for Research and Education 
    The project is looking at the mechanisms of glutamate receptor-induced excitotoxicity and identify potential points of intervention to prevent ischemic cell death. The parent grant supports work entirely in male animals and mixed sex cultures; however, brain injury resulting from stroke is known to affect female brains differently than male brains. The supplement will add female cells and mice to explore whether sex differences are modulated by female vs. male genotype or by estrogen, a female sex hormone.