Sex Differences in the Metabolic Syndrome

代谢综合征的性别差异

• 批准号: 10004046
• 负责人: Karen Reue
• 金额: $ 152.02万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004046
• 关键词: Adipose tissue; Biological; Biological Markers; Blood; Cardiovascular Diseases; Central obesity; ChIP-seq; Cholesterol; Chromosomes; Clinical; Clinical Research; Cohort Studies; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Dose; Dyslipidemias; Educational workshop; Ensure; Enzymes; Estradiol; Estrogen Receptors; Estrogens; Exhibits; Fatty Liver; Female; Fostering; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Gonadal Steroid Hormones; Grant; Health; Healthcare; Histones; Hormones; Human; Hypertension; Incidence; Individual; Insulin Resistance; Investigation; LCN2 gene; Lead; Leadership; Libraries; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mitochondria; Morbidity - disease rate; Mouse Strains; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Ploidies; Population; Pre-Clinical Model; Predisposition; Pyruvate Kinase; Regulation; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Secondary to; Sex Bias; Sex Chromosomes; Sex Differences; Site; Skeletal Muscle; System; Technology; Testing; Tissue Sample; Tissues; Treatment Efficacy; United States; Woman; X Inactivation; adipokines; blood lipid; cardiometabolism; career; cohort; combat; diabetes risk; disorder risk; energy balance; epigenetic regulation; gene interaction; genetic approach; genetic variant; genotypic sex; human tissue; male; men; mortality; mouse model; obesity development; optimal treatments; personalized medicine; potential biomarker; precision medicine; programs; response; sex; therapeutic target; therapy development; trait; transcriptome sequencing; translational study; treatment strategy

PROJECT SUMMARY - Overall: Sex Differences in the Metabolic Syndrome The objective of our SCORE on “Sex Differences in the Metabolic Syndrome” is to elucidate sex differences in risk factors and treatments for Metabolic Syndrome (MetSyn) components such as obesity, insulin resistance/diabetes, dyslipidemia, and fatty liver. Differences between men and women in susceptibility to cardio-metabolic disease are well known, but the underlying genetic and physiological mechanisms remain poorly defined. Our goal is to identify factors that determine sex-specific MetSyn risk, which may lead to better diagnosis and treatment for both sexes. A unique feature of our program is the investigation of sex differences in MetSyn from multiple perspectives, including effects of estrogen, of XX vs. XY sex chromosome complement, and of genetic variation. Our program consists of three research projects and three cores, and will use preclinical models and human tissue samples. Project 1, “Sex chromosome effects on metabolic syndrome risk and treatment,” will build on the finding that the presence of XX compared to XY chromosomes increases susceptibility to obesity and related traits. Much of the XX effect is attributable to the Kdm5c gene, which escapes X chromosome inactivation and encodes a histone modifying enzyme. Our studies will define the effects of Kdm5c dose on the epigenetic regulation of gene expression, energy balance, and adipose tissue remodeling during obesity. They will also elucidate the XX chromosome effect on increased female risk for diabetes secondary to statin drug therapy, and test a dietary co-therapy that may alleviate this sex-biased adverse drug response. Project 2, “Gene-by-sex interactions in mitochondrial functions and metabolic traits,” seeks to understand the roles of both genetics and sex in MetSyn traits. Results of a “systems genetics” approach have implicated sex- and tissue-specific action of specific genes on MetSyn traits. Our studies will elucidate sex effects on mitochondrial functions in insulin resistance, sex-specific effects of the adipokine lipocalin 2 on adiposity and insulin resistance, and the sex-specific role of the PKLR pyruvate kinase in hepatic steatosis. The gene-by-sex interactions discovered in the mouse will be tested in tissues from human cohorts. Project 3, “The impact of estrogen receptor (ER)  in metabolic health,” will test the hypothesis that muscle ER protects against metabolic dysfunction in mice and women, will identify ER regulatory sites across the genome in females and males, and elucidate the effect of ER on the regulation of mitochondrial function. Results may provide proof-of-concept evidence that skeletal muscle ER is an effective therapeutic target to combat metabolic dysfunction and type 2 diabetes. The Genomic Technologies Core will perform RNA-seq, ChIP-seq and related technologies for all three projects. The Career Enhancement Core will foster research in sex differences in metabolism by administering a Pilot & Feasibility grant program, and through courses, workshops, and a free library of videos. The Administrative Core will ensure effective leadership and management of this SCORE.

项目摘要 - 总体：代谢综合征的性别差异 我们“代谢综合征中的性别差异”SCORE 的目标是阐明性别 代谢综合征 (MetSyn) 的危险因素和治疗方法存在差异，例如肥胖、 胰岛素抵抗/糖尿病、血脂异常和脂肪肝。男女易感性差异 心脏代谢疾病的发生是众所周知的，但潜在的遗传和生理机制仍然存在 定义不明确。我们的目标是确定决定性别特异性 MetSyn 风险的因素，这可能会带来更好的结果 两性的诊断和治疗。我们计划的一个独特之处是对性别差异的调查 在 MetSyn 中，从多个角度进行分析，包括雌激素、XX 与 XY 性染色体的影响 互补和遗传变异。我们的计划由三个研究项目和三个核心组成， 将使用临床前模型和人体组织样本。项目 1，“性染色体对代谢的影响” 综合征风险和治疗”将建立在 XX 染色体与 XY 染色体相比的存在基础上 增加对肥胖和相关特征的易感性。大部分 XX 效应可归因于 Kdm5c 基因， 它逃避 X 染色体失活并编码组蛋白修饰酶。我们的研究将定义 Kdm5c 剂量对基因表达、能量平衡和脂肪的表观遗传调控的影响 肥胖期间的组织重塑。他们还将阐明 XX 染色体对女性风险增加的影响 对于继发于他汀类药物治疗的糖尿病，并测试可能减轻这种性别偏见的饮食联合疗法 药物不良反应。项目 2，“线粒体功能和代谢特征中基因与性别的相互作用” 旨在了解遗传和性别在 MetSyn 特征中的作用。 “系统遗传学”的结果 该方法表明特定基因对 MetSyn 性状的性别和组织特异性作用。我们的研究将 阐明性别对胰岛素抵抗中线粒体功能的影响，脂肪因子的性别特异性影响 脂质运载蛋白 2 对肥胖和胰岛素抵抗的影响，以及 PKLR 丙酮酸激酶在肝脏中的性别特异性作用 脂肪变性。在小鼠中发现的基因与性别之间的相互作用将在人类组织中进行测试。 项目 3“雌激素受体 (ER)  对代谢健康的影响”将检验以下假设：肌肉 ERα 可防止小鼠和女性的代谢功能障碍，将识别整个系统中的 ERα 调节位点 研究人员对女性和男性的基因组进行了研究，并阐明了 ERα 对线粒体功能调节的影响。 结果可能提供概念验证证据，证明骨骼肌 ERα 是一种有效的治疗靶点 对抗代谢功能障碍和 2 型糖尿病。基因组技术核心将执行 RNA-seq、 所有三个项目的 ChIP-seq 和相关技术。职业发展核心将促进研究 通过管理试点和可行性资助计划以及通过课程来了解新陈代谢中的性别差异， 研讨会和免费视频库。行政核心将确保有效的领导和 该 SCORE 的管理。