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.

整体 总结 我们关于“心脏代谢健康和疾病的性别差异”的SCORE的目的是确定 决定性别特异性心脏代谢疾病风险的因素，这可能导致更好的诊断， 对两性的治疗。我们的计划的一个独特之处是从多个性别差异的调查 观点，包括雌激素的影响，XX与XY性染色体基因，和遗传变异 在个体之间。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（iPSC）和现有的人类群体数据集 （基因组学，转录组学，蛋白质组学和代谢组学）将我们的模型系统中的发现转化为 人类项目1，“心脏代谢疾病的表观遗传性决定因素和预防”，将建立在我们的 确定X和Y染色体基因，影响饮食发展和 诱发肥胖和对他汀类药物副作用的易感性。我们将阐明三个X-Y的作用 组蛋白去甲基化酶基因在肥胖小鼠和人脂肪细胞表观遗传性别差异中作用 分化我们还将确定性别偏见的他汀类药物对女性的不良影响的表观遗传决定因素。 线粒体功能项目2，“射血分数正常的心力衰竭中基因与性别的相互作用 （HFpEF），”旨在了解女性HFpEF患病率增加的潜在机制 与男人相比。使用“系统遗传学”方法和一组遗传上不同的小鼠品系， 目的是在分子水平上了解HFpEF特征的性别差异，包括性腺的作用， 激素和性染色体，并创建性别特异性生物网络，可以推广到 人类最近的研究结果表明，线粒体酶ACSL 6的性别差异是HFpEF的原因， 进一步的研究将描述线粒体功能障碍在HFpEF中的作用。项目3，“国际合作的影响 雌激素受体α对心肌细胞代谢和健康的影响，”将检验雌激素 心肌细胞中的α受体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敲除或过表达小鼠的发现 然后，将与我们的人类翻译生物信息学合作，将模型与人类数据相结合 核心人类翻译生物信息学核心将作为计算分析的中心， 将三个项目的发现转化为与人类心脏代谢特征相关的发现， 现有的大型人类基因组学数据集。职业提升核心将促进性研究 通过管理试点和可行性资助计划，并将教育研究人员 通过课程、实验室“训练营”和SABV视频库向学生介绍SABV。的 行政核心将确保对该评分的有效领导和管理。