The impact of estrogen receptor alpha on cardiomyocellular metabolism and health

项目3：雌激素受体α对心肌细胞代谢和健康的影响 ESR1（编码ERα）的失活突变和减少与 女性和男性的心脏代谢疾病风险。此外，更年期的过渡会减少 心脏代谢健康和心力衰竭发病率增加。然而，潜在的因果机制 女性在此生命阶段的心力衰竭风险，以及受损伤影响的特定细胞类型， 雌激素的作用还没有被充分定义。由于心脏代谢的下降，包括胰岛素 抵抗、肥胖和心功能障碍在ERα基因敲除小鼠中重现，我们的实验室 随后进行了组织解剖方法，以了解ERα作用的细胞特异性影响 对新陈代谢和组织功能的影响在这项提案中，我们特别关注ERα对心脏的作用， 功能关于雌二醇在心脏组织中作用的先前报道的主要局限性是缺乏 体内心肌细胞中ERα操纵的特异性。为了克服这一局限性，我们 第一个实验室产生具有条件性心肌细胞特异性敲低（hERαKD）的小鼠，或 Esr1的过度表达（hERαOE）。在本提案的目标1中，我们将确定hERαKD对以下方面的影响： 线粒体代谢、心脏组织完整性和心脏功能。我们假设 心肌细胞敲除Esr1破坏线粒体代谢导致致病性转变 在底物代谢、炎症、纤维化和对心脏毒性的损害作用的易感性方面， 药物（如阿霉素）。在目标2中，我们将确定条件性心肌细胞特异性 Esr1、hERαOE过表达对线粒体代谢、心脏组织完整性和保护作用 对抗高脂饮食和心脏毒性剂。重要的是，这些小鼠的表型结果 结合人类受试者的发现，模型将使我们能够确定ERα调节的 研究ER α在心脏转录组中的表达，并建立ERα对新靶基因的调控机制。总体 我们工作的目标是确定雌激素受体作用受损在乳腺癌病理生物学中的影响。 心力衰竭和确定治疗机会目标，以保护妇女免受心脏代谢性疾病 疾病

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.