Myocyte specific regulation of metabolism and the response to biomechanical force

肌细胞代谢的特异性调节和对生物力学力的反应

• 批准号: 9269244
• 负责人: Monte S Willis
• 金额: $ 38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2018-04-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269244
• 关键词: Apoptosis; Attention; Autophagocytosis; Biomechanics; Calcium; Calpain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Congestive Heart Failure; Disease; Evolution; Family member; Functional disorder; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; High Fat Diet; Human; Injury; JUN gene; Knowledge; MAPK8 gene; Mediating; Metabolic; Metabolism; Microfilaments; Mission; Mitochondria; Modeling; Molecular; Monoubiquitination; Mus; Muscle; Muscle Cells; Myocardial Ischemia; Myocardium; Nuclear; Nuclear Export; Nuclear Receptors; PPAR alpha; PPAR gamma; PPAR-beta; Pathogenesis; Pathologic; Patients; Performance; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Post-Translational Protein Processing; Predisposition; Production; Protein Family; Protein Isoforms; Proteins; Proteomics; Public Health; Quality Control; Regulation; Renin-Angiotensin-Aldosterone System; Reperfusion Injury; Research; Resistance; Ring Finger Domain; Role; Running; Signal Transduction; Societies; Specificity; Speed; Stress; System; Testing; Therapeutic; Transcription Factor AP-1; Transgenic Mice; Treatment Failure; Ubiquitin; Ubiquitin family; Ubiquitination; United States National Institutes of Health; base; diabetic cardiomyopathy; in vivo; innovation; left ventricular assist device; metabolomics; misfolded protein; multicatalytic endopeptidase complex; muscle RING finger 1; novel; protein degradation; public health relevance; response; tool; transcription factor; ubiquitin ligase

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.

描述（由适用提供）：心脏病仍然是我们社会中最常见的死亡原因。虽然疗法在过去几十年中仔细演变，但这种进化与越来越多的慢性心力衰竭患者的创造相似。我们对肾素 - 血管紧张素 - 醛固酮系统以外的疾病病理生理的更广泛理解对于开发其他工具以治疗心力衰竭是必要的。角色 泛素蛋白质组系统（UPS）和自噬在保持心脏中关键蛋白质质量控​​制功能方面的自动噬，由于错误折叠蛋白在心力衰竭的发病机理中的明显作用，引起了人们的注意。但是，我们对UPS和自噬系统如何通过泛素连接酶指导的理解有很大的差距，泛素连接酶是对这两种系统的特殊性的蛋白质。该项目的广泛长期目标是描述肌肉环（MURF）泛素连接酶调节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泛素连接酶是调节的PPARα，PPARß/δ和PPARγ1活性，控制线粒体ROS，并且与自噬有关以在上下文中保护心脏衰竭中的心肌细胞。推论假设是，抑制MURF1可能明确预防CALPAIN1诱导的心力衰竭，以在体内提供更特异性的心脏保护抗Calpain1靶标。我们的假设预测，抑制特定MURF活性可能对心力衰竭有害，而PPAR信号传导对其发病机理（糖尿病心肌病）至关重要，或者在CALPAIN1是介导心力衰竭（缺血再灌注损伤）的情况下有用。中央假设将通过完成以下特定目标（SA）来检验：（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）确定分子机制MURF1依赖性Calpain1活性调节心脏线粒体功能和ROS。 （3）确定心脏MURF1的机制可调节体内自噬，以增强心脏对缺血再灌注损伤和心力衰竭的抗性。对于SA1，我们将表征MURF2和MURF3在高脂肪饮食引起的糖尿病心肌病中受到保护的机制。对于SA2，我们将确定MURF1依赖性CalPain1在调节ROS，线粒体动力学和EEF2中的作用。 SA3研究了MURF1调节自噬的机制，以整合抑制MURF1的其他方式可能在心力衰竭中受到背景保护。本研究提供了创新的范式，阐明了MURF蛋白可能针对其在心力衰竭背景下保护心脏的能力的机制。