Myocyte specific regulation of metabolism and the response to biomechanical force

描述（由申请人提供）：心脏病仍然是我们社会中最常见的死亡原因。虽然在过去的几十年里，治疗方法有了很大的发展，但这种发展已经导致越来越多的慢性心力衰竭患者的出现。我们对疾病的病理生理学的更广泛的理解超越了肾素-血管紧张素-醛固酮系统，这对于开发治疗心力衰竭的其他工具是必要的。的作用 由于错误折叠蛋白在心力衰竭发病机制中的明显作用，泛素蛋白酶体系统（UPS）和自噬在维持心脏中关键蛋白质质量控制功能中的作用已经获得越来越多的关注。然而，我们对UPS和自噬系统如何由泛素连接酶指导的理解存在很大的差距，泛素连接酶是为这两个系统提供特异性的蛋白质。该项目的广泛长期目标是阐明心力衰竭背景下肌肉无名指（MuRF）遍在蛋白连接酶调节PPARα、PPARß/δ和PPARγ1活性、线粒体动力学和自噬的机制。基于我们的初步研究，我们的中心假设是MuRF泛素连接酶调节PPARα、PPAR 4/δ和PPARγ1的活性，控制线粒体ROS，并参与自噬以在心力衰竭时保护心肌细胞。一个必然的假设是，抑制MuRF 1可以特异性地防止钙蛋白酶1诱导的心力衰竭，以提供更特异性的体内心脏保护性抗钙蛋白酶1靶点。我们的假设预测，抑制特定的MuRF活性可能在心力衰竭中是有害的，其中PPAR信号传导是其发病机制的核心（糖尿病心肌病），或者在钙蛋白酶1介导心力衰竭（缺血再灌注损伤）时是有益的。通过完成以下特定目的（SA）来检验中心假设：（1）阐明MuRF家族泛素连接酶在糖尿病心肌病和心力衰竭中的独特作用。(2)确定MuRF 1依赖的Calpain 1活性调节心脏线粒体功能和ROS的分子机制。(3)确定心脏MuRF 1在体内调节自噬以增强心脏对缺血再灌注损伤和心力衰竭的抵抗力的机制。对于SA 1，我们将描述MuRF 2和MuRF 3在高脂饮食诱导的糖尿病心肌病中的保护机制。对于SA 2，我们将确定MuRF 1依赖性Calpain 1在心力衰竭中调节ROS、线粒体动力学和eEF 2的作用。SA 3研究了MuRF 1调节自噬的机制，以整合抑制MuRF 1可能在心力衰竭中具有背景保护作用的其他方式。目前的研究提供了创新的范例，阐明了MuRF蛋白可能靶向其在心力衰竭背景下保护心脏的能力的机制。

DESCRIPTION (provided by applicant): Heart disease remains the most common cause of death in our society. While therapies have evolved considerably over the past decades, this evolution has paralleled the creation of a growing number of patients with chronic heart failure. Our broader understanding of the pathophysiology of disease beyond the renin- angiotensin-aldosterone system is necessary to develop additional tools to treat heart failure. The role of the ubiquitin proteasome system (UPS) and autophagy in maintaining critical protein quality control functions in the heart has gained increasing attention due to the apparent role of misfolded proteins in the pathogenesis of heart failure. However, there is a broad gap in our understanding of how the UPS and autophagy systems are directed by ubiquitin ligases, the proteins that give specificity to both systems. The broad long-term goal of this project is to delineate the mechanisms that Muscle Ring Finger (MuRF) ubiquitin ligases regulate PPARα, PPARß/δ, and PPARγ1 activities, mitochondrial dynamics, and autophagy in the context of heart failure. Based on our preliminary studies, our central hypothesis is that the MuRF ubiquitin ligases are regulate PPARα, PPARß/δ, and PPARγ1 activities, control mitochondrial ROS, and are involved in autophagy to contextually protect cardiomyocytes in heart failure. A corollary hypothesis is that inhibiting MuRF1 may specifically protect against Calpain1-induced heart failure to provide a more specific cardioprotective anti-Calpain1 target in vivo. Our hypothesis predicts that inhibiting specific MuRF activities may be detrimental in heart failure where PPAR signaling is central to its pathogenesis (diabetic cardiomyopathy) or helpful where Calpain1 is mediates heart failure (ischemia reperfusion injury). The central hypothesis will be tested by completing the following Specific Aims (SA): (1) Elucidate the unique roles of MuRF family ubiquitin ligases in diabetic cardiomyopathy and heart failure. (2) Determine the molecular mechanisms MuRF1-dependent Calpain1 activity regulates cardiac mitochondrial function and ROS. (3) Determine the mechanisms cardiac MuRF1 regulates autophagy in vivo to enhance the heart's resistance to ischemia reperfusion injury and heart failure. For SA1, we will characterize the mechanisms MuRF2 and MuRF3 are protective in a high fat diet induced diabetic cardiomyopathy. For SA2, we'll determine the role of MuRF1-dependent Calpain1 in regulating ROS, mitochondrial dynamics, and eEF2 in heart failure. SA3 investigates the mechanisms MuRF1 regulates autophagy to integrate additional ways in which inhibiting MuRF1 may be contextually protective in heart failure. The present studies offer innovative paradigms elucidating the mechanisms in which MuRF proteins may be targeted for their ability to protect the heart in the context of heart failure.