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

基本信息

批准号：
8479424
负责人：
Monte S Willis
金额：
$ 34.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8479424
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

项目摘要

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. .

描述（由申请人提供）：研究及相关其他项目信息 6. 项目摘要/摘要心脏肥大是心力衰竭最常见的前兆，是心脏对多种外在刺激的反应，包括高血压、瓣膜性心脏病和心肌梗塞。在此过程中会同时发生脂肪酸氧化受损和葡萄糖利用增加，主要受转录因子过氧化物酶体增殖物激活受体 (PPAR) 家族的调节。目前尚不清楚在心脏肥大发展过程中调节 PPAR 转录因子活性降低的机制。在本提案中，我们将首先确定心脏特异性肌环指 1 (MuRF1) 泛素化 PPAR 复合物的机制，靶向其蛋白酶体依赖性降解。这些发现随后将使用我们建立的 MuRF1 -/- 和 MuRF1 心脏转基因小鼠系在体内得到证实。 MuRF1 表达对 PPAR 调节的脂肪酸和葡萄糖氧化的作用将通过检测灌注放射性标记脂肪酸和葡萄糖的分离工作心脏制剂中的氧化代谢物来确定。在本研究的第二个目标中，我们将确定在心脏肥大期间调节心脏 MuRF1 增加的信号通路，重点关注 NF-B、FOXO 和 FAK/MAPK 信号通路。然后，我们将确定压力过载如何影响 MuRF1 和 PPAR- 活性以及心脏肥大中的定位，以阐明 MuRF1 相互作用和调节 PPAR- 或 PPAR- 复合物的其他成分的机制。最后，我们将通过将心肌细胞的机械拉伸与 MuRF1 的增加联系起来，阐明压力过载诱导脂肪酸和葡萄糖氧化变化的具体机制。在具体目标三中，我们将展示拉伸通过转录上调 MuRF1 水平以及拉伸诱导 MuRF1 从肌节易位到细胞质和细胞核来增加 MuRF1 活性的机制。然后，我们将确定 MuRF1 在机械拉伸过程中如何与核 PPAR- 相互作用，通过特定目标 #1（MuRF1 泛素化 PPAR- 以及随后被蛋白酶体降解）和特定目标 #2（如何stretch 通过 NF-kB 和 FOXO 信号通路调节 MuRF1 水平。这些研究将首次确定各种心脏病引起的机械应力如何通过肌联蛋白相关泛素连接酶 MuRF1 导致脂肪酸和葡萄糖氧化的特征性变化。。