Sex Differences in the Metabolic Syndrome

代谢综合征的性别差异

基本信息

批准号：
10447051
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
项目类别：
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/10447051
关键词：
Adipose tissue Biological Biological Markers Cardiometabolic Disease Cardiovascular Diseases Central obesity ChIP-seq Chromosomes Clinical Clinical Research Cohort Studies Development Diabetes Mellitus Diagnosis 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 United States Woman X Inactivation adipokines blood lipid career cohort combat diabetes risk dietary disorder risk energy balance epigenetic regulation gene interaction genetic approach genetic variant genotypic sex human tissue hypercholesterolemia male men mortality mouse model obesity development optimal treatments personalized medicine potential biomarker precision medicine programs response sex therapeutic target therapeutically effective therapy development trait transcriptome sequencing translational study treatment strategy

项目摘要

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分数的目的是“代谢综合征的性别差异”的目的是阐明性别代谢综合征（METSYN）成分（例如肥胖）的危险因素和治疗差异，胰岛素抵抗/糖尿病，血脂异常和脂肪肝。在敏感性中男人和女人之间的差异众所周知的是心脏代谢疾病，但潜在的遗传和物理机制仍然存在定义不佳。我们的目标是确定确定性别特定性梅赛风险的因素，这可能会导致更好两性的诊断和治疗。我们计划的一个独特功能是对性别差异的调查从多个角度来看，包括XX与XY性别染色体的多种角度，包括雌激素的影响补体和遗传变异。我们的计划包括三个研究项目和三个核心，以及将使用临床前模型和人体组织样品。项目1，“性染色体对代谢的影响综合征风险和治疗方法将建立在与XY染色体相比的发现的基础上增加对肥胖和相关特征的敏感性。 XX效应的大部分归因于KDM5C基因，逃脱了X染色体灭活并编码修饰酶的组蛋白。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节的影响肥胖期间的组织重塑。他们还将阐明XX染色体对增加女性风险的影响仅用于他汀类药物疗法的糖尿病，并测试饮食中的饮食疗法，可能会减轻这种性偏见不良药物反应。项目2，“线粒体功能和代谢性状中的基因相互作用”，试图了解遗传学和性别在Metsyn特征中的作用。 “系统遗传学”的结果方法已经实施了特定基因对METSYN特征的性别和组织特异性作用。我们的研究将阐明对胰岛素抵抗性线粒体功能的性别影响，脂肪因子的性别特异性作用 Lipocalin 2在肥胖和胰岛素抵抗方面，PKLR丙酮酸激酶在肝中的性别特异性作用脂肪变性。在小鼠中发现的基因相互作用将在人类人群的组织中进行测试。项目3，“雌激素受体（ER）在代谢健康中的影响”将检验肌肉的假设 ER防止小鼠和妇女的代谢功能障碍，将确定整个整个监管部位女性和雄性中的基因组，并阐明了ERR对线粒体功能调节的影响。结果可能会提供概念验证证据，证明骨骼肌ERR是一个有效的治疗靶点战斗代谢功能障碍和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。职业增强核心将促进研究通过管理飞行员和可行性赠款计划以及通过课程，在新陈代谢的性别差异中，讲习班和免费视频库。行政核心将确保有效的领导和该分数的管理。