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: 8132395
• 负责人: Monte S Willis
• 金额: $ 36.04万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132395
• 关键词: Affect; Biomechanics; Cardiac; Cardiac Myocytes; Cardiac Output; Cause of Death; Cell Nucleus; Characteristics; Complex; Cytoplasm; Data; Dependence; Development; Diagnosis; Disease; Energy Metabolism; Energy-Generating Resources; Enzymes; Failure; Family; Fatty Acids; Free Radicals; Genes; Genetic Transcription; Glucose; Heart; Heart Hypertrophy; Heart Valve Diseases; Heart failure; Hypertension; Hypertrophy; Impairment; In Vitro; Label; Lead; Link; Location; MAPK Signaling Pathway Pathway; Mechanical Stimulation; Mechanical Stress; Mechanics; Mediating; Metabolic; Metabolism; Muscle; Muscle Cells; Myocardial Infarction; Myocardium; NF-kappa B; Nuclear; Nuclear Receptors; Oxidative Stress; PTK2 gene; Pathologic; Pathology; Peroxisome Proliferator-Activated Receptors; Preparation; Process; Proteins; Radio; Regulation; Research; Ring Finger Domain; Role; Sarcomeres; Signal Pathway; Small Interfering RNA; Stimulus; Stress; Stretching; Study Section; Time; Transgenic Mice; Ubiquitin; Ubiquitination; United States; Up-Regulation; Work; abstracting; connectin; cost; fatty acid oxidation; glucose metabolism; heart function; in vivo; multicatalytic endopeptidase complex; novel; novel therapeutics; oxidation; pressure; public health relevance; receptor; response; therapy development; transcription factor; ubiquitin ligase

DESCRIPTION (provided by applicant): RESEARCH & RELATED Other Project Information 6. Project Summary/Abstract The development of cardiac hypertrophy, the most common precursor to heart failure, is a response of the heart to a wide range of extrinsic stimuli, including hypertension, valvular heart disease, and myocardial infarction. Parallel impairment in fatty acid oxidation and an increase in glucose utilization occur during this process, regulated primarily by the peroxisome proliferator-activated receptor (PPAR) family of transcription factors. The mechanism(s) that regulates this decrease in PPAR transcription factor activity during the development of cardiac hypertrophy is presently unknown. In this proposal, we will first identify the mechanism(s) by which the cardiac specific Muscle Ring Finger-1 (MuRF1) ubiquitinates the PPAR- complex, targeting its proteasome-dependent degradation. These findings will then be confirmed in vivo using our established MuRF1 -/- and MuRF1 cardiac transgenic mouse lines. The role of MuRF1 expression on PPAR-regulated fatty acid and glucose oxidation will then be determined by detecting oxidation metabolites from isolated working heart preparations perfused with radio-labeled fatty acid and glucose. In the second aim of this study, we will determine the signaling pathways which regulate increases in cardiac MuRF1 during cardiac hypertrophy, focusing on NF-B, FOXO, and FAK/MAPK signaling pathways. We will then determine how pressure overload affects MuRF1 and PPAR- activity and localization in cardiac hypertrophy, to elucidate the mechanisms by which MuRF1 interacts and regulates PPAR-, or other components of the PPAR- complex. Lastly, we will elucidate specific mechanisms by which pressure overload induces changes in fatty acid and glucose oxidation by linking the mechanical stretch of cardiomyocytes to increases in MuRF1. In specific aim three, we will demonstrate the mechanisms by which stretch increases MuRF1 activity by its up-regulation of MuRF1 levels transcriptionally and through the stretch-induced translocation of MuRF1 from the sarcomere into the cytoplasm and nucleus. We will then determine how MuRF1 interacts with nuclear PPAR- during mechanical stretch to regulate fatty acid and glucose oxidation through the mechanisms identified in specific aim #1 (MuRF1 ubiquitination of PPAR- and subsequent degradation by the proteasome) and specific aim #2 (how stretch regulates MuRF1 levels through NF- kB and FOXO signaling pathway). These studies will identify for the first time how mechanical stress from a variety of cardiac pathologies leads to characteristic changes in fatty acid and glucose oxidation through the titin-associated ubiquitin ligase MuRF1. . PUBLIC HEALTH RELEVANCE: RESEARCH & RELATED Other Project Information and Project Narrative. Heart failure is a leading cause of death in the United States, affecting approximately 5.2 million people, with an approximately 60,000 new cases diagnosed each year, costing an estimated $33.2 billion in 2007. While significant changes in metabolism occur during the development of heart failure and its most common precursor cardiac hypertrophy, the underlying mechanisms that regulate these changes are not clearly delineated. Elucidating these novel mechanisms as proposed in this study will help identify targets for the development of therapies for this common disease.

描述（由申请人提供）： 研究与相关的其他项目信息6。项目摘要/摘要心脏肥大的发展是心力衰竭的最常见前体，是心脏对广泛的外在刺激的反应，包括高血压，瓣膜心脏病和心肌梗死。在此过程中，脂肪酸氧化和葡萄糖利用率增加的平行障碍主要由转录因子的过氧化物酶体增殖物激活受体（PPAR）家族调节。目前尚不清楚，在心脏肥大发展过程中调节PPAR转录因子活性下降的机制是未知的。在此提案中，我们将首先确定心脏特异性肌肉环1（MURF1）泛素化的机制将其靶向其蛋白酶体依赖性降解。然后，将使用我们已建立的MURF1 - / - 和MURF1心脏转基因小鼠系在体内确认这些发现。然后，将通过检测来自分离的工作心脏制剂中的氧化代谢物来确定MURF1表达在PPAR调节的脂肪酸和葡萄糖氧化中的作用，并用无线电标记的脂肪酸和葡萄糖灌注。在这项研究的第二个目标中，我们将确定心脏肥大期间心脏MURF1增加的信号通路，重点是NF-B，FOXO和FAK/MAPK信号通路。然后，我们将确定压力超负荷如何影响MURF1和心脏肥大中的PPAR活性和定位，以阐明MURF1相互作用并调节PPAR-或PPAR-COMPLECT的其他成分的机制。最后，我们将阐明特定机制，通过将心肌细胞的机械拉伸与MURF1的增加联系，压力超负荷通过将脂肪酸和葡萄糖氧化引起变化。在特定目标三中，我们将通过转录的MURF1水平的上调以及Murf1从Saromere从Saromere转录到细胞质和核的拉伸诱导的易位，从而证明拉伸的MURF1活性增加了MURF1活性。然后，我们将在机械拉伸过程中确定MURF1如何与核PPAR相互作用，以通过特定目标1（Murf1泛素化PPAR-泛素化PPAR-蛋白酶体和随后的蛋白酶体降解）和特定的AIM＃2（如何通过NF-KB和Fox fox Signally path来调节MURF1水平）。这些研究将首次确定各种心脏病理学的机械应力如何通过钛相关的泛素连接酶Murf1导致脂肪酸和葡萄糖氧化的特征变化。 。 公共卫生相关性： 研究及相关的其他项目信息和项目叙述。 心力衰竭是美国的主要死亡原因，影响了约520万人，每年诊断出约60,000例新病例，估计成本为332亿美元。虽然代谢在心力衰竭的发展及其最常见的前体心脏肥大及其最常见的前体肥大，但调节这些变化的基础机制并未显然是这些变化。阐明本研究中提出的这些新型机制将有助于确定为这种常见疾病开发疗法的靶标。