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The impact of estrogen receptor alpha on cardiomyocellular metabolism and health

雌激素受体α对心肌细胞代谢和健康的影响

基本信息

批准号：
10713760
负责人：
Andrea L Hevener
金额：
$ 39.49万
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 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713760
关键词：
ATP Synthesis Pathway Aerobic Aerobic Exercise Age Aging Animals Antineoplastic Agents Architecture Breast Cancer Patient Calcium Cardiac Cardiac Myocytes Cardiac Output Cardiometabolic Disease Cardiomyopathies Cardiotoxicity Carnitine Cells Chemotherapy-Oncologic Procedure Chronic Disease Clinical Collaborations Complex Complication Crista ampullaris Cytochrome c Reductase DNA Damage Data Set Deuterium Disease Dissection Doxorubicin EFRAC ESR1 gene Echocardiography Electron Microscopy Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Exercise Tolerance Fatty acid glycerol esters Fibrosis Functional disorder Funding Genes Genome Genus Hippocampus Goals Health Heart Heart failure High Fat Diet Histology Homeostasis Hypertrophy Immune Impairment Incidence Inflammation Insulin Resistance Iron Isoproterenol Isotopes Knockout Mice Label Laboratories Life Link Liver Membrane Menopause Metabolic Metabolism Mitochondria Mitochondrial DNA Mitochondrial Proteins Molecular Mus Muscle Mutation Myocardial dysfunction Nuclear Obesity Outcome Pathogenicity Pathology Pathway Analysis Pathway interactions Perimenopause Phase Phenotype Postmenopause Predisposition Premature Menopause Proteins Proteome Proteomics Purines Quality Control Radiolabeled Regulation Reporting Research Respiration Respiratory Chain Ribonucleotides Risk Role Sex Differences Skeletal Muscle Specificity Testing Tissues Toxic effect Transcript VO2max Woman Women&apos s Health Work cardiometabolism cell type combat comparative density design disorder risk fatty acid metabolism fatty acid oxidation feeding heart function heart metabolism human subject improved in vivo insight insulin sensitivity knock-down lipid metabolism malignant breast neoplasm men metabolomics mitochondrial dysfunction mitochondrial metabolism mouse model multiple omics novel novel strategies overexpression preservation prevent proteostasis targeted treatment tool transcriptome transcriptome sequencing transcriptomics

项目摘要

Project 3: The impact of estrogen receptor alpha on cardiomyocellular metabolism and health ABSTRACT Inactivating mutations and reductions in ESR1 (encodes ERα) are associated with cardiometabolic disease risk in women and men. Moreover, the menopausal transition drives reduction of cardiometabolic health and increased heart failure incidence. However, the causal mechanisms underlying heart failure risk in women during this life phase, and the specific cell types impacted by impairment in estrogen action are inadequately defined. Since aspects of cardiometabolic decline including insulin resistance, obesity, and cardiac dysfunction are recapitulated in ERα null mice, our laboratory has subsequently performed a tissue dissection approach to understand the cell-specific impact of ERα action on metabolism and tissue function. In this proposal we focused specifically on the role of ERα on cardiac function. A primary limitation regarding previous reports of estradiol action in cardiac tissue is the lack of specificity in the manipulation of ERα in cardiomyocytes in vivo. To overcome this limitation, we are the first laboratory to generate mice with a conditional cardiomyocellular-specific knockdown (hERαKD) or overexpression (hERαOE) of Esr1. In Aim 1 of this proposal we will determine the impact of hERαKD on mitochondrial metabolism, cardiac tissue integrity, and heart function. We hypothesize that cardiomyocellular knockdown of Esr1 disrupts mitochondrial metabolism contributing to pathogenic shifts in substrate metabolism, inflammation, fibrosis, and susceptibility to the damaging effects of cardiotoxic agents (e.g. Doxorubicin). In Aim 2 we will determine the impact of conditional cardiomyocellular-specific overexpression of Esr1, hERαOE, on mitochondrial metabolism, cardiac tissue integrity, and protection against high fat diet feeding and cardiotoxic agents. Importantly, phenotypic outcomes in these mouse models, integrated with findings in human subjects, will allow us to ascertain the ERα-regulated transcriptome in heart and establish mechanisms of ERα control over novel target genes. The overarching goal of our work is to determine the impact of impaired estrogen receptor action in the pathobiology of heart failure and identify targets of therapeutic opportunity to protect women against cardiometabolic disease.

项目3：雌激素受体α对心肌细胞代谢和健康的影响