新线粒体蛋白ES1对心肌肥厚小鼠保护作用的研究

Cardiac hypertrophy is a major risk factor in the development of congestive heart failure. Defects in the function of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure. However, our understanding of the regulation of ATP synthase in the energy demanding heart under normal and pathological conditions remains poor. Better understanding of novel regulation of ATP synthase may lead to new therapeutic approaches in fighting heart disease. We discovered an unknown function protein ES1, our preliminary studies revealed that ES1 is a mitochondrial protein, which is associated with the ATP synthase F1 sector by interaction with subunits alpha and beta. We further demonstrated that ES1 levels are related to ATP synthase activates. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in hypertrophic hearts. Based on these observations, we hypothesize that ES1 is a key player in cardiac physiology by modulating mitochondrial function. We plan to test our hypothesis by pursuing the studies to determine whether ES1 plays a crucial role in the development of pressure overload-induced cardiac hypertrophy and the transition to CHF and what is the mechanisms by which ES1 protect the heart from cardiac dysfunction and pathological development under pressure overload condition. Our studies will likely overcome barriers in understanding the molecular mechanisms of ATP synthase regulation in the intact animals. This will provide novel insights into how to manipulate the energy production machine to slow the progression of pathological cardiac hypertrophy and congestive heart failure.

心肌肥厚是导致心脏衰竭的重要危险因素。ATP合成酶的功能缺失会导致和引发多种疾病，例如心肌病和心力衰竭。在生理和病理条件下对ATP合成酶在心脏能量调节过程中的研究非常有限。对ATP合成酶功能及其调控的深入研究有利于发现更好的治疗心脏相关疾病的方法。本课题组发现未知功能蛋白ES1基因定位于细胞线粒体内，能与ATP合成酶F1组件的alpha和beta亚基发生相互作用， ES1的表达与ATP合成酶的活性相关。ES1在心肌肥厚的样本中表达显著的减少。综上，我们推测生理条件下ES1在线粒体功能调节上起到重要的作用。本研究试图通过研究压力超负荷引起的病理性心肌肥厚和心功能损伤条件下ES1对心脏保护的作用及其机理来证实这一假设。本课题能深入的研究动物体内ATP合成酶功能和调控的分子机理，为对基于能量缺失引发的心肌肥厚和心衰的治疗提供新的有效的思路和理论基础。

心肌肥厚是导致心脏衰竭的重要危险因素。ATP合酶的功能缺失会导致和引发多种疾病，例如心肌病和心力衰竭。在生理和病理条件下对ATP合酶在心脏能量调节过程中的研究非常有限。对ATP合酶功能及其调控的深入研究有利于发现更好的治疗心脏相关疾病的方法。本研究发现线粒体蛋白ES1基因定位于细胞线粒体内，能与ATP合成酶F1组件的alpha和beta亚基发生相互作用， ES1的表达能调节ATP合酶的活性，细胞内过表达ES1后，合成ATP活性增强，而水解ATP活性减弱。ES1在心肌肥厚的人组织样本和心脏压力负荷小鼠模型心脏组织样本中表达显著的减少。综上所述，本研究证实生理条件下ES1在线粒体功能调节上起到重要的作用。本研究通过压力超负荷引起的病理性心肌肥厚和心功能损伤模型，发现ES1对心脏保护的作用是通过调控ATP合酶的活性和线粒体能量代谢实现的。本课题深入的研究了动物体内ATP合酶功能和调控的分子机理，为对基于能量缺失引发的心肌肥厚和心衰的治疗提供新的有效的思路和理论基础。