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：
10597663
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/10597663
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 Estrogen decline 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 Macrophage 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 Perimenopause Phenotype Polymerase Positioning Attribute Postmenopause 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 feeding immune health improved inhibitor insight insulin sensitivity interest iron metabolism male men mitochondrial metabolism mouse model new therapeutic target novel novel strategies obesity development overexpression prevent 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）的降低表达与代谢功能障碍和男女疾病的风险增加。然而，在代谢功能障碍和特定组织（S）会议ERα介导对代谢，感染和胰岛素作用的影响的特定组织中，ERα水平降低的因果机制仍未得到定义。我们已经表明，在全身ESR1 - / - 小鼠（ESR1编码ERα）中概括了代谢综合征，包括胰岛素抵抗，组织注射和肥胖的各个方面。随后，我们进行了一种组织解剖方法，以了解ERα作用对炎症和代谢稳态的细胞特异性影响。由于巨噬细胞（Mφ）是一种关键细胞类型调节组织代谢，并且参与了心脏代谢相关疾病的病理生物学，因此在此，我们建议在此处询问ERα调节Mφ的机制，以特定的侧重于M线粒体代谢和MTDNA重复的机制。在AIM 1中，我们将使用损失 - （MACER）和 - ESR1（ERαMyetg）表达方法来选择性地调节雄性和雌性小鼠髓样谱系中的ERα。我们将研究 ERα对代谢稳态的表达响应高脂肪饮食的喂养，并确定整个身体ESR1 - / - 小鼠模型中ERα的恢复是否可以逆转肥胖和胰岛素抵抗表型。 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 （催化亚基）。由于我们的研究表明在不同细胞类型中的分子结果与ERα缺失的对比，因此该提案的主要目标是更好地了解ERα在控制Mφ中专门控制线粒体功能方面的作用，并确定ERα动作受损会导致注射和代谢功能障碍与与心脏病性疾病易感性相关的女性，尤其是在Menopaus in Menopa中。