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Epigenetic sex determinants of cardiometabolic disease and prevention

心脏代谢疾病的表观遗传性别决定因素及其预防

基本信息

批准号：
10713758
负责人：
Karen Reue
金额：
$ 39.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713758
关键词：
Address Adipocytes Adipose tissue Adverse effects Adverse event Area Binding Sites Bioinformatics Biology Body Composition Cardiometabolic Disease Cardiovascular Diseases Cell Line Cells Childhood Chromatin Chromosomes Collaborations Conceptions Data Development Diabetes Mellitus Disease Drug Prescriptions Drug Side Effects Dyslipidemias Embryo Enhancers Enzymes Epigenetic Process Estrogens Exhibits Female Fetus Gene Dosage Gene Expression Regulation Genes Genomics Goals Gonadal Hormones Health Histones Hormones Human Human Genetics In Vitro Length Modification Molecular Mus Obesity Outcome Patients Pharmaceutical Preparations Physiological Ploidies Prevalence Prevention Preventive treatment Regulation Research Personnel Resources Risk Factors Role Sex Bias Sex Chromosomes Sex Differences Tail Testosterone Translating Woman Work X Chromosome Y Chromosome adipocyte differentiation cardiometabolism cardiovascular disorder prevention cardiovascular disorder risk differential expression dosage energy balance epigenetic regulation epigenomics gonad development histone demethylase histone methylation human female human male in vivo induced pluripotent stem cell lipid biosynthesis male men mitochondrial dysfunction mouse model multiple omics obesity development optimal treatments prevent promoter response sex therapy development trait transcription factor transcriptome transcriptomics translation to humans

项目摘要

PROJECT 1: Epigenetic Sex Differences in Cardiometabolic Disease and Prevention SUMMARY Sex impacts the development of obesity and related cardiometabolic disorders. Sex also influences adverse responses to statin drugs, which are widely prescribed to prevent cardiovascular disease. We have identified genes on the sex chromosomes (X and Y) that have differential expression levels between males and females and influence both adiposity and adverse effects of statin drugs. The sex chromosome genes Kdm5c, Kdm6a, and Kdm5d encode histone demethylase enzymes, which regulate methyl marks on histone tails to modulate transcription factor access to gene promoters and enhancers. We hypothesize that gene dosage of X and Y chromosome histone demethylases impacts sex differences in cardiometabolic health by epigenetic regulation of gene expression. We will define the mechanisms by which sex-specific gene dosage of these enzymes influence adipose tissue biology and statin induced mitochondrial dysfunction. The goal of Aim1 is to elucidate epigenetic sex differences in mouse adiposity and human adipocyte differentiation. We will determine physiological and molecular effects of Kdm5c, Kdm6a and Kdm5d gene dosage on sex differences in adiposity and adipocyte differentiation using mouse models, multi-omics analyses, and human induced pluripotent stem cell (iPSC) lines. Specific objective include: determining the physiological mechanisms by which Kdm6a influences adiposity exclusively in females, and Kdm5d influences adiposity exclusively in males; identifying the genomic targets of KDM5C, KDM6A, and KDM5D in adipocytes by characterizing the transcriptome, chromatin landscape, histone methylation, and histone demethylase genomic binding sites; and identifying sex differences in human male and female preadipocyte differentiation and epigenetic landscape using a unique resource of several dozen human iPS cell lines. The goal of Aim 2 is to evaluate epigenetic determinants of sex-biased statin adverse effects. We will utilize human iPSCs from women with and without statin new-onset diabetes to assess the role of KDM5 histone demethylase activity in statin-induced mitochondrial dysfunction, and to identify transcriptomic and epigenomic modifications in statin-treated iPSCs from women with or without statin new onset diabetes and mitochondrial dysfunction. These studies address the understudied area of sex differences in adverse effects of widely prescribed drugs. We will translate our findings on fundamental mechanisms underlying sex differences in cardiometabolic traits to humans through analysis of extensive existing human genetic and –omics data, in collaboration with our Human Translational Bioinformatics Core.

项目1：心脏代谢疾病和预防的表观遗传性别差异