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Principal Investigator: Karen Reue
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $1,467,135
Funding agency: National Heart Lung and Blood Institute
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
Administrative Core will ensure effective leadership and management of this SCORE.
Terms: <Adverse effects><Apoplexy><Bio-Informatics><Bioinformatics><Biologic Models><Biological><Biological Models><Body Tissues><Brain Vascular Accident><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Toxicity><Cardiac artery><Cardiac infarction><Cardiocyte><Cardiometabolic Disease><Cardiometabolic Disorder><Cardiomyopathies><Cardiotoxic><Cardiotoxicity><Cardiovascular Diseases><Cell Line><CellLine><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Collaborations><Communication><Computer Analysis><Coronary><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary artery><Data><Data Set><Dedications><Development><Diagnosis><Differences between sexes><Differs between sexes><Disease><Disorder><Dissection><Drugs><EFRAC><ERalpha><ERα><ESR1><ESR1 gene><Ejection Fraction><Endocrine Gland Secretion><Ensure><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogens><Experimental Models><Female><Fostering><Gender Bias><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic defect><Genomics><Goals><Gonadal Hormones><Gonosomes><Grant><Health><Heart Muscle Cells><Heart artery><Heart failure><Heart myocyte><Hormones><Human><Human Genetics><Individual><Intermediary Metabolism><Investigation><Investigators><Knock-out><Knockout><Laboratories><Leadership><Libraries><Medication><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microvascular Dysfunction><Mitochondria><Model System><Modern Man><Molecular><Mouse Strains><Murine><Mus><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardiopathies><NR3A1><Obesity><Operations Research><Pharmaceutical Preparations><Population><Predisposition><Prevalence><Prevention><Preventive><Process><Proteomics><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Risk><Role><Series><Sex Bias><Sex Chromosomes><Sex Differences><Sexual differences><Strains Cell Lines><Stress cardiomyopathy><Stroke><Students><Susceptibility><System><Takotsubo><Testing><Therapeutic Estrogen><Therapeutic Hormone><Tissues><Translating><Woman><Y Chromosome><adipocyte development><adipocyte differentiation><adiposity><atherosclerotic coronary disease><biologic><brain attack><cardiac failure><cardiac function><cardiac infarct><cardiometabolic><cardiometabolism><cardiomyocyte><cardiovascular disorder><career><cell type><cerebral vascular accident><cerebrovascular accident><comparing females and males><comparing women and men><computational analyses><computational analysis><computer analyses><conference><convention><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><corpulence><cultured cell line><develop therapy><developmental><diet-associated obesity><diet-induced obesity><diet-related obesity><disease risk><disorder risk><drug/agent><epigenetic regulation><epigenetically><females compared to males><females compared with males><females versus males><females vs males><function of the heart><genetic approach><genetic strategy><genome mutation><heart attack><heart function><heart infarct><heart infarction><hiPSC><histone demethylase><human data><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human model><improved><induced human pluripotent stem cells><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><insight><intervention development><knock-down><knockdown><meeting><meetings><men><metabolism measurement><metabolomics><metabonomics><microvascular complications><microvascular disease><mitochondrial><mitochondrial dysfunction><mitochondrial metabolism><model of human><mortality><mouse model><murine model><myocardium disease><myocardium disorder><overexpress><overexpression><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pre-clinical><preclinical><preservation><programs><response><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><small vessel disease><social role><stress-induced cardiomyopathy><stroked><strokes><summit><symposia><symposium><therapeutic agent development><therapeutic development><therapy development><trait><transcriptomics><treatment development><women compared to men><women compared with men><women versus men><women vs men>