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差异概括性影响肥胖和相关心脏代谢疾病的发展。性也影响对手对他汀类药物的反应，该药物被广泛规定以预防心血管疾病。我们已经确定了男性和女性之间具有差异表达水平的性染色体（X和Y）上的基因并影响他汀类药物的肥胖和不良影响。性染色体基因KDM5C，KDM6A， KDM5D编码组蛋白脱甲基酶，该酶在组蛋白尾部调节甲基标记以调节转录因子访问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脱甲基酶会影响心脏代谢健康的性别差异。基因表达的调节。我们将定义这些特定性别基因剂量的机制酶会影响脂肪组织生物学和他汀类药物诱导的线粒体功能障碍。 AIM1的目标是阐明小鼠肥胖和人脂肪细胞分化的表观遗传性差异。我们将确定KDM5C，KDM6A和KDM5D基因剂量对性别差异的物理和分子作用使用小鼠模型，多矩分析和人类诱导的肥胖和脂肪细胞分化多能干细胞（IPSC）线。具体目标包括：确定物理机制 KDM6A仅影响女性的肥胖，而KDM5D仅影响男性的肥胖。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，Hisstone甲基化和Hisstone脱甲基酶基因组结合位点；和确定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个人IPS细胞系的独特资源。目标2的目的是评估表观遗传学性别偏见的他汀类药物不良反应的决定因素。我们将利用有或没有的女性的人类IPSC 他汀类药物新发育糖尿病评估KDM5 Hisstone脱甲基酶活性在他汀类药物诱导的线粒体功能障碍，并识别他汀类药物处理的IPSC中的转录组和表观基因组修饰来自有或没有他汀类药物新发作糖尿病和线粒体功能障碍的女性。这些研究解决了广泛处方药的不良反应中性别差异的研究领域。我们将翻译我们的发现关于通过分析对人类心脏代谢特征的性别差异的基本机制与我们的人类翻译生物信息学合作，广泛的现有人类遗传和 - 组数据核。