Overall SUMMARY The objective of our SCORE on “Sex Differences in Cardiometabolic Health and Disease” is to identify factors that determine sex-specific cardiometabolic disease risk, which may lead to better diagnosis and treatment for both sexes. A unique feature of our program is the investigation of sex differences from multiple perspectives, including effects of estrogen, of XX vs. XY sex chromosome genes, and of genetic variation among individuals. Our program consists of three research projects and three cores, and will use preclinical mouse models, human induced pluripotent stem cell lines (iPSCs), and existing human population datasets (genomic, transcriptomic, proteomic, and metabolomic) to translate findings from our model systems to humans. Project 1, “Epigenetic sex determinants of cardiometabolic disease and prevention,” will build on our identification of X and Y chromosome genes that influence sex differences in both the development of diet- induced obesity and susceptibility to adverse effects of statin drugs. We will elucidate the role of three X-Y histone demethylase genes in epigenetic sex differences in mouse adiposity and human adipocyte differentiation. We will also identify the epigenetic determinants of sex-biased statin adverse effects on mitochondrial function. Project 2, “Gene-by-sex interactions in heart failure with preserved ejection fraction (HFpEF),” seeks to understand the mechanisms underlying increased prevalence of HFpEF in women compared to men. Using a “systems genetics” approach and a panel of genetically distinct mouse strains, the goals are to understand sex differences in HFpEF traits at the molecular level, including the role of gonadal hormones and sex chromosomes, and to create sex-specific biologic networks that can be generalized to humans. Recent findings implicate sex differences in the mitochondrial enzyme, ACSL6, as causal for HFpEF, and further studies will characterize the role of mitochondrial dysfunction in HFpEF. Project 3, “The impact of estrogen receptor alpha on cardiomyocellular metabolism and health,” will test the hypothesis that estrogen receptor alpha action in cardiomyocytes impacts mitochondrial metabolism, cardiac tissue integrity and heart function. Findings with unique cardiomyocyte estrogen receptor alpha knockout or overexpression mouse models will then be integrated with human data in collaboration with our Human Translational Bioinformatics Core. The Human Translational Bioinformatics Core will serve as hub for computational analyses to translate findings from the three Projects for association and relevant to cardiometabolic traits in humans using existing large human genetic and –omics datasets. The Career Enhancement Core will foster research in sex differences in metabolism by administering a Pilot & Feasibility grant program, and will educate researchers and students about SABV through courses, hands-on laboratory ‘bootcamp,’ and a library of SABV videos. The Administr...