Sex Differences in the Metabolic Syndrome

代谢综合征的性别差异

• 批准号: 10225900
• 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/10225900
• 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

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.

项目总结-总体：代谢综合征的性别差异