Sex Differences in Cardiometabolic Health and Disease

心脏代谢健康和疾病的性别差异

• 批准号: 10713757
• 负责人: Karen Reue
• 金额: $ 149.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10713757
• 关键词: Adverse effects; Bioinformatics; Biological; Biological Models; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Cell Line; Collaborations; Communication; Computer Analysis; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Data Set; Dedications; Development; Diagnosis; Disease; Dissection; EFRAC; Ensure; Enzymes; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Experimental Models; Female; Fostering; Genes; Genetic; Genetic Variation; Genomics; Goals; Gonadal Hormones; Grant; Health; Heart failure; Hormones; Human; Human Genetics; Individual; Investigation; Knock-out; Laboratories; Leadership; Libraries; Metabolism; Microvascular Dysfunction; Mitochondria; Molecular; Mouse Strains; Mus; Mutation; Myocardial Infarction; Obesity; Operations Research; Patients; Pharmaceutical Preparations; Population; Predisposition; Prevalence; Prevention; Preventive; Process; Proteomics; Publishing; Research; Research Personnel; Research Project Grants; Risk; Role; Series; Sex Bias; Sex Chromosomes; Sex Differences; Stress cardiomyopathy; Stroke; Students; System; Testing; Tissues; Translating; Woman; Y Chromosome; adipocyte differentiation; cardiometabolism; career; cell type; diet-induced obesity; disorder risk; epigenetic regulation; genetic approach; heart function; histone demethylase; human data; human model; improved; induced pluripotent stem cell; insight; knock-down; meetings; men; metabolomics; mitochondrial dysfunction; mitochondrial metabolism; mortality; mouse model; overexpression; pre-clinical; preservation; programs; response; sex; symposium; therapeutic development; therapy development; trait; transcriptomics

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.

总括 摘要 我们对心脏代谢健康和疾病中的性别差异进行评分的目的是确定 决定特定性别心脏代谢性疾病风险的因素，这可能导致更好的诊断和 对男女都适用的治疗。我们节目的一个独特之处是从多个不同的角度调查性别差异 前景，包括雌激素的影响，XX与XY性染色体基因的影响，以及遗传变异 在个人之间。我们的计划包括三个研究项目和三个核心，并将使用临床前 小鼠模型、人类诱导多能干细胞系(IPSCs)和现有的人类种群数据集 (基因组、转录组、蛋白质组和代谢组学)将我们的模型系统的研究结果转化为 人类。项目1“心脏代谢性疾病的表观遗传性决定因素和预防”将建立在我们的 X和Y染色体基因在两种饮食发育中影响性别差异的鉴定 诱导性肥胖和他汀类药物不良反应的易感性。我们将阐明三个X-Y的作用 组蛋白去甲基酶基因在小鼠肥胖和人脂肪细胞表观遗传性别差异中的作用 差异化。我们还将确定性别偏见的他汀类药物不良影响的表观遗传决定因素 线粒体功能。项目2，“在射血分数保留的心力衰竭患者中，基因与性别的相互作用 旨在了解女性HFpEF患病率增加的机制 与男人相比。利用“系统遗传学”的方法和一组基因不同的小鼠品系， 目的是在分子水平上了解HFpEF性状的性别差异，包括性腺的作用 荷尔蒙和性染色体，并创建性别特异的生物网络，可以概括为 人类。最近的发现表明，线粒体酶ACSL6的性别差异是导致HFpEF的原因， 进一步的研究将确定线粒体功能障碍在HFpEF中的作用。项目3，“ 雌激素受体α对心肌细胞新陈代谢和健康的影响“将检验雌激素的假说 心肌细胞中受体α的作用影响线粒体代谢、心脏组织完整性和心脏 功能。独特的心肌细胞雌激素受体α基因敲除或过表达小鼠的研究结果 然后，模型将与人类数据集成，并与我们的人类翻译生物信息学合作 核心。人类翻译生物信息学核心将作为计算分析的枢纽 翻译来自三个项目的结果，以便与人类的心脏代谢特征相关联和相关 现有的大型人类基因和组学数据集。职业提升核心将促进性方面的研究 通过管理一项试点和可行性拨款计划，研究新陈代谢的差异，并将教育研究人员 学生通过课程、动手实验室“训练营”和SABV录像库了解SABV。这个 管理核心将确保有效地领导和管理这一分数。