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: 9130225
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130225
• 关键词: Apoptosis; Attention; Autophagocytosis; Biomechanics; Calcium; Calpain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Congestive Heart Failure; Disease; Evolution; Family; Family member; Functional disorder; Goals; Health; 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; Mono-S; Mus; Muscle; Muscle Cells; Myocardial Ischemia; Myocardium; Nuclear; Nuclear Export; Nuclear Receptors; PPAR alpha; PPAR delta; PPAR gamma; PPAR-beta; Pathogenesis; 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; Stream; Stress; System; Testing; Transcription Factor AP-1; Transgenic Mice; Ubiquitin; Ubiquitination; base; diabetic cardiomyopathy; in vivo; innovation; left ventricular assist device; metabolomics; multicatalytic endopeptidase complex; novel; protein degradation; protein misfolding; response; tool; transcription factor; ubiquitin ligase; ubiquitin-protein 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（由申请人提供）：心脏病仍然是我们社会中最常见的死亡原因，尽管在过去几十年里治疗方法有了很大的发展，但这种发展与我们对慢性心力衰竭患者的越来越多的认识同步发生。为了开发治疗心力衰竭的其他工具，有必要了解肾素-血管紧张素-醛固酮系统以外疾病的病理生理学。 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的蛋白质质量控​​制功能方面受到越来越多的关注。 UPS 和自噬系统由泛素连接酶指导，泛素连接酶赋予这两个系统特异性，该项目的长期目标是描绘肌肉环指 (MuRF) 的机制。泛素连接酶在心力衰竭的情况下调节 PPARα、PPARβ/δ 和 PPARγ1 活性、线粒体动力学和自噬 根据我们的初步研究，我们的中心假设是 MuRF 泛素连接酶调节 PPARα、PPARβ/δ 和 PPARγ1。活性，控制线粒体 ROS，并参与自噬，从而在心力衰竭时保护心肌细胞。 MuRF1 可以特异性地预防 Calpain1 诱导的心力衰竭，从而在体内提供更具体的心脏保护性抗 Calpain1 靶标。我们的假设预测，抑制特定 MuRF 活性可能会导致心力衰竭（其中 PPAR 信号传导是其发病机制的核心）（糖尿病心肌病）或心力衰竭。 Calpain1 介导心力衰竭（缺血再灌注损伤）时有帮助。中心假设将通过完成以下具体目标 (SA) 进行检验：(1) 阐明 MuRF 的独特作用。 (2)确定MuRF1依赖性Calpain1活性调节心脏线粒体功能和ROS的分子机制。(3)确定心脏MuRF1调节体内自噬增强心脏对缺血再灌注损伤的抵抗力的机制。对于 SA1，我们将描述 MuRF2 和 MuRF3 在高脂肪饮食诱发的糖尿病心肌病中的保护机制。 SA2，我们将确定 MuRF1 依赖性 Calpain1 在调节 ROS、线粒体动力学和 eEF2 在心力衰竭中的作用 SA3 研究 MuRF1 调节自噬的机制，以整合抑制 MuRF1 可能在心力衰竭中发挥保护作用的其他方式。研究提供了创新范例，阐明了 MuRF 蛋白可能因其在心力衰竭情况下保护心脏的能力而成为靶点的机制。