Cardiac and Skeletal Muscle Metabolism and Proteolysis in Heart Failure

描述（由申请人提供）：本提案详细介绍了一个全面的5年培训计划，为我的职业发展，在学术心血管医学。在哥伦比亚大学医学中心完成心血管医学的临床培训后，我计划开始一项指导研究计划，为生物医学研究的独立职业提供必要的额外科学培训。我将获得细胞生物学，遗传学，分子生物化学，代谢和体内生理学方面的深入经验，适用于慢性心力衰竭患者的代谢紊乱和运动耐量。唐娜·曼奇尼博士和伊拉·戈德堡博士将指导我的科学和职业发展。Mancini博士是心力衰竭和移植，运动生理学和心血管疾病代谢领域的国际公认领导者，并在学术医学和基础科学方面拥有成功的职业指导记录。伊拉戈德堡博士是糖尿病血管和心肌代谢以及胰岛素信号传导方面的专家。此外，一个由心血管和临床基础科学家（Andrew Marks、伊拉塔巴斯、Ulrich Jorde、Yoshifuma纳卡、金哲真博士）和管理人员（Jamie Rubin博士）组成的咨询委员会将提供科学和职业建议。本申请的中心假设是，常见的基因表达模式和代谢紊乱决定了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装置放置改善血流动力学后是可逆的。以前，我已经表明，在骨骼肌的局部合成代谢功能在心力衰竭受损，进行性肌肉萎缩的发展，通过激活肌肉蛋白水解。我的目标是：1）研究泛素-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）评估心室辅助装置放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水解的影响。相关性（见说明）：心力衰竭是一种正在扩大的全球流行病，在美国已经影响了500多万人。运动不耐受和肌肉萎缩是外周代谢受损的结果，是心力衰竭死亡率的预测因子。本研究旨在了解骨骼肌和心肌代谢和功能的基本相互作用，最终目标是发现新的治疗方法来预防或治疗心力衰竭患者的功能下降。 (End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)