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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：心血管代谢疾病及其预防的表观遗传性别差异概括性别影响肥胖和相关心脏代谢疾病的发展。性别也会产生不利影响对他汀类药物的反应，他汀类药物被广泛用于预防心血管疾病。我们已经确定性染色体（X 和 Y）上的基因在男性和女性之间具有差异表达水平并影响肥胖和他汀类药物的不良反应。性染色体基因 Kdm5c、Kdm6a、 Kdm5d 编码组蛋白去甲基化酶，可调节组蛋白尾部的甲基标记以调节转录因子接近基因启动子和增强子。我们假设 X 和 Y 的基因剂量染色体组蛋白去甲基化酶通过表观遗传影响心脏代谢健康的性别差异基因表达的调控。我们将定义这些性别特异性基因剂量的机制酶影响脂肪组织生物学和他汀类药物引起的线粒体功能障碍。 Aim1 的目标是阐明小鼠肥胖和人类脂肪细胞分化的表观遗传性别差异。我们将确定 Kdm5c、Kdm6a 和 Kdm5d 基因剂量对性别差异的生理和分子影响使用小鼠模型、多组学分析和人类诱导的肥胖和脂肪细胞分化多能干细胞 (iPSC) 系。具体目标包括：确定生理机制 Kdm6a 仅影响女性肥胖，Kdm5d 仅影响男性肥胖；通过表征脂肪细胞中 KDM5C、KDM6A 和 KDM5D 的基因组靶标转录组、染色质景观、组蛋白甲基化和组蛋白去甲基化酶基因组结合位点；和识别人类男性和女性前脂肪细胞分化和表观遗传景观的性别差异使用数十种人类 iPS 细胞系的独特资源。目标 2 的目标是评估表观遗传性别偏见的他汀类药物不良反应的决定因素。我们将利用来自患有和不患有这种疾病的女性的人类 iPSC 他汀类药物新发糖尿病评估 KDM5 组蛋白去甲基化酶活性在他汀类药物诱导的糖尿病中的作用线粒体功能障碍，并鉴定他汀类药物治疗的 iPSC 中的转录组和表观基因组修饰来自使用或不使用他汀类药物的女性新发糖尿病和线粒体功能障碍。这些研究涉及广泛处方药物不良反应中性别差异的研究尚未充分。我们将转化我们的发现通过分析人类心脏代谢特征性别差异的基本机制与我们的人类转化生物信息学合作，广泛现有的人类遗传和组学数据核。