Cardiac and Skeletal Muscle Metabolism and Proteolysis in Heart Failure

心力衰竭中的心肌和骨骼肌代谢和蛋白水解

基本信息

批准号：
7885368
负责人：
P. Christian Schulze
金额：
$ 13.54万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7885368
关键词：
Academic Medical Centers Activities of Daily Living Administrator Advisory Committees Affect Animal Model Atrophic Basic Science Biochemistry Biomedical Research Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular system Cell Respiration Cellular Structures Cellular biology Chronic Clinical Cytokine Activation Diabetes Mellitus Energy Metabolism Epidemic Exercise Exercise Physiology Exercise Tolerance Functional disorder Gene Expression Glucose Goals Growth Growth Factor Heart failure Human Instruction Insulin Resistance Insulin-Like Growth Factor I Intracellular Accumulation of Lipids Investigation Lead Link Mediating Medicine Mentors Mentorship Metabolic Metabolic Pathway Metabolism Molecular Molecular Genetics Morbidity - disease rate Morphology Muscle Muscle Weakness Muscle function Muscular Atrophy Myocardial Myocardium Patients Pattern Peripheral Physiology Play Prevalence Proteins Proteolysis Regulation Research Research Personnel Risk Role Scientist Secondary to Signal Transduction Skeletal Muscle System Testing Therapeutic Training Training Programs Transplantation Ubiquitin Ubiquitin-mediated Proteolysis Pathway Work abstracting career career development experience fatty acid metabolism functional decline functional disability hemodynamics in vivo insulin signaling metabolic abnormality assessment mortality multicatalytic endopeptidase complex muscle metabolism novel prevent prognostic programs protein degradation skeletal skeletal muscle wasting ventricular assist device wasting

项目摘要

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in academic Cardiovascular Medicine. After completion of clinical training in Cardiovascular Medicine at Columbia University Medical Center, I plan to embark on a mentored research program to provide additional scientific training necessary for an independent career in biomedical research. I will gain in-depth experience in cellular biology, genetics, molecular biochemistry, metabolism, and in vivo physiology as applied to derangements of metabolism and exercise tolerance in patients with chronic heart failure. Drs. Donna Mancini and Ira Goldberg will mentor my scientific and career development. Dr. Mancini is an internationally recognized leader in the fields of heart failure and transplant, exercise physiology and metabolism in cardiovascular diseases, and has a proven track record for successful career mentorship in academic medicine and the basic sciences. Dr. Ira Goldberg is an expert in vascular and myocardial metabolism and insulin signaling in diabetes mellitus. In addition, an advisory committee of established basic cardiovascular and clinician scientists (Drs. Andrew Marks, Ira Tabas, Ulrich Jorde, Yoshifuma Naka, Zhezhen Jin) and administrators (Dr. Jamie Rubin) will provide scientific and career advice. The central hypothesis of this application is that common gene expression patterns and metabolic derangements determine structural and functional changes in skeletal muscle and myocardium of patients with HF and that those changes are reversible after hemodynamic improvement through ventricular assist device placement. Previously, I have shown that local anabolic function in skeletal muscle is impaired in heart failure and that progressive muscle wasting develops through activation of muscle proteolysis. My aims are: 1) To characterize the role of the ubiquitin-proteasome-system in skeletal muscle atrophy in patients with heart failure; 2) To analyze metabolic changes in atrophying skeletal muscle of patients with heart failure; 3) To assess the impact of hemodynamic improvement after ventricular assist device placement on myocardial and skeletal muscle metabolism and proteolysis in patients with heart failure. RELEVANCE (See instructions): Heart failure is an expanding worldwide epidemic that already affects more than 5 million people in the US. Exercise intolerance and muscle wasting result from impaired peripheral metabolism and are predictors of mortality in heart failure. This research aims to understand the fundamental interactions of skeletal muscle and myocardial metabolism and function with the ultimate goal of discovering new therapies to prevent or treat the functional decline in patients with heart failure. (End of Abstract)

描述（由申请人提供）：该提案详细介绍了我在学术心血管医学职业发展的5年培训计划。在哥伦比亚大学医学中心完成心血管医学临床培训后，我计划着手进行一项指导的研究计划，以提供生物医学研究独立职业所需的其他科学培训。我将在细胞生物学，遗传学，分子生物化学，代谢和体内生理学方面获得深入的经验，以应用于慢性心力衰竭患者的代谢和运动耐受性的危险。博士。唐娜·曼奇尼（Donna Mancini）和伊拉·戈德堡（Ira Goldberg）将指导我的科学和职业发展。 Mancini博士是心力衰竭，运动生理学和代谢在心血管疾病领域的国际公认领导者，并且在学术医学和基本科学领域成功的职业指导有了可靠的往绩。 Ira Goldberg博士是糖尿病中血管和心肌代谢和胰岛素信号的专家。此外，建立的基本心血管和临床科学家的咨询委员会（Andrew Marks博士，Ira Tabas，Ulrich Jorde，Ulrich Jorde，Naka，Yoshifuma Naka，Zhezhen Jin）和行政人员（Jamie Rubin博士）将提供科学和职业建议。该应用的中心假设是，常见的基因表达模式和代谢扰动决定了HF患者骨骼肌和心肌的结构和功能变化，并且这些变化在通过心室辅助设备放置后进行血液动力学改善后可逆。以前，我已经表明，骨骼肌中局部合成代谢功能在心力衰竭中受到损害，并且通过激活肌肉蛋白水解而发展肌肉浪费。我的目的是：1）表征心力衰竭患者中泛素 - 蛋白酶体系统在骨骼肌萎缩中的作用； 2）分析心力衰竭患者的骨骼肌肉萎缩肌肉的代谢变化； 3）评估心室肌肉代谢和骨骼肌代谢和蛋白水解对心脏衰竭患者的心肌和骨骼肌代谢和蛋白水解的影响。相关性（请参阅说明）：心力衰竭是一种不断扩大的全球流行病，已经影响了美国超过500万人。锻炼不耐受性和肌肉浪费是由于周围代谢受损而导致的，并且是心力衰竭死亡率的预测指标。这项研究旨在了解骨骼肌和心肌代谢和功能的基本相互作用，其最终目的是发现新疗法，以防止或治疗心力衰竭患者的功能下降。（抽象的结尾）