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The impact of ERalpha on mitochondrial function in macrophages

ERα对巨噬细胞线粒体功能的影响

基本信息

批准号：
10366022
负责人：
Andrea L Hevener
金额：
$ 39万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366022
关键词：
Adipocytes Adipose tissue Aging Agonist Anabolism Animals Aorta Area Arterial Fatty Streak Atherosclerosis Biological Assay Bone Marrow Breast Cardiometabolic Disease Catalytic Domain Cell physiology Cells Chronic Chronic Disease Clinical Core Facility Data Development Disease Disease susceptibility Dissection Estrogen Receptor alpha Estrogen Receptors Estrogens Female Genes Goals Health High Fat Diet Homeostasis Hormone replacement therapy Human Immunomodulators Impairment Incidence Inflammation Inflammatory Insulin Insulin Resistance Interleukin-1 Iron Liver Mediating Menopause Metabolic Metabolic dysfunction Metabolic syndrome Metabolism Mitochondria Mitochondrial DNA Modeling Molecular Morphology Mus Muscle Cells Myelogenous Myeloid Cells Nuclear Obese Mice Obesity Outcome Pathway interactions Phenotype Polymerase Positioning Attribute Production Proteins Proteomics RNA Regulation Regulatory Element Research Role Signal Transduction Spleen Technology Testing Tissues Woman Work animal resource cardiometabolism cell type chromatin immunoprecipitation combat design differential expression disorder risk estrogen disruption feeding immune health improved inhibitor insight insulin sensitivity interest iron metabolism macrophage male men mitochondrial metabolism mouse model new therapeutic target novel novel strategies obesity development overexpression prevent receptor expression reproductive response restoration selective expression sex tool weapons

项目摘要

Reductions in estrogen receptor (ER) expression are associated with metabolic dysfunction and heightened disease risk in women and men. However, the causal mechanisms underlying reduced ERα levels in the context of metabolic dysfunction and the specific tissue(s) conferring ERα-mediated effects on metabolism, inflammation, and insulin action remain inadequately defined. We have shown that aspects of the metabolic syndrome including insulin resistance, tissue inflammation, and obesity are recapitulated in whole body Esr1-/- mice (Esr1 encodes ERα). We have subsequently performed a tissue dissection approach to understand the cell-specific impact of ERα action on inflammation and metabolic homeostasis. Because macrophages (MΦ) are a key cell type regulating tissue metabolism, and are involved in the pathobiology of cardiometabolic-related diseases, herein we propose to interrogate the mechanisms by which ERα modulates MΦ function with a specific focus on M mitochondrial metabolism and mtDNA replication. In Aim 1 we will use loss- (MACER) and gain-of-Esr1 (ERαMyeTg) expression approaches to selectively modulate ERα in the myeloid lineage of male and female mice. We will examine the impact of ERα expression on metabolic homeostasis in response to high fat diet feeding and determine whether restoration of ERα in myeloid cells of the whole body Esr1-/- mouse model can reverse the obesity and insulin resistance phenotype. Since we were the first to identify that ER regulates mitochondrial dynamics and mtDNA replication in myocytes and adipocytes, and since mitochondria are viewed as central signaling hubs regulating immunometabolism, in Aim 2 we will interrogate the role of ERα in controlling fission/fusion/mitophagy dynamics and mtDNA replication by polymerase γ, Polg1 (catalytic subunit). Since our research shows contrasting molecular outcomes to ERα deletion in different cell types, a primary goal of this proposal is to better understand the role of ERα in controlling mitochondrial function specifically in MΦ, as well as determine how impaired ERα action drives inflammation and metabolic dysfunction with relevance to cardiometabolic disease susceptibility, especially in women during the menopausal transition.

雌激素受体（ER）表达减少与代谢功能障碍和