Cardiac and Skeletal Muscle Metabolism and Proteolysis in Heart Failure

描述(由申请者提供)：这份建议书详细说明了我在学术心血管内科的职业发展的5年综合培训计划。在哥伦比亚大学医学中心完成心血管医学临床培训后，我计划开始一项有指导的研究计划，为独立的生物医学研究生涯提供必要的额外科学培训。我将在细胞生物学、遗传学、分子生物化学、新陈代谢和体内生理学方面获得深入的经验，应用于慢性心力衰竭患者的代谢紊乱和运动耐量。唐娜·曼奇尼博士和艾拉·戈德伯格博士将指导我的科学和职业发展。曼奇尼博士在心力衰竭和移植、运动生理学和心血管疾病新陈代谢领域是国际公认的领导者，在学术医学和基础科学领域拥有成功的职业指导记录。Ira Goldberg博士是糖尿病血管和心肌代谢及胰岛素信号方面的专家。此外，一个由基础心血管和临床科学家(安德鲁·马克斯博士、艾拉·塔巴斯博士、乌尔里希·乔德博士、Yoshiuma Naka博士、金哲真博士)和管理人员(杰米·鲁宾博士)组成的咨询委员会将提供科学和职业建议。这一应用的中心假设是，常见的基因表达模式和代谢紊乱决定了心力衰竭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放置脑室辅助装置改善血流动力学后是可逆的。在此之前，我已经证明，在心力衰竭时，骨骼肌的局部合成代谢功能会受到损害，而进行性肌肉萎缩是通过激活肌肉蛋白分解来实现的。我的目标是：1)确定泛素-蛋白酶体系统在心力衰竭患者骨骼肌萎缩中的作用；2)分析心力衰竭患者萎缩骨骼肌的代谢变化；3)评估放置脑室辅助装置后血流动力学改善对心力衰竭患者心肌和骨骼肌代谢及蛋白分解的影响。相关性(参见说明)：心力衰竭是一种在全球范围内不断扩大的流行病，已经影响到美国500多万人。运动不耐受和肌肉萎缩是外周新陈代谢受损的结果，是心力衰竭死亡率的预测指标。本研究旨在了解骨骼肌与心肌代谢和功能的基本相互作用，最终目的是发现新的治疗方法来预防或治疗心力衰竭患者的功能衰退。(摘要结束)

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)