Cardiac and Skeletal Muscle Metabolism and Proteolysis in Heart Failure

这份建议书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 心血管内科在哥伦比亚完成心血管医学临床培训后 大学医学中心，我计划开始一项指导研究计划，以提供更多的科学 在生物医学研究的独立职业所必需的培训。我将获得深入的经验， 细胞生物学、遗传学、分子生物化学、代谢和体内生理学， 慢性心力衰竭患者的代谢紊乱和运动耐量唐娜医生 曼奇尼和伊拉戈德堡将指导我的科学和职业发展。曼奇尼医生是国际上 心脏衰竭和移植，运动生理学和代谢领域的公认领导者， 心血管疾病，并有良好的记录，成功的职业导师在学术 医学和基础科学。伊拉戈德堡博士是血管和心肌代谢方面的专家， 糖尿病中的胰岛素信号传导。此外，还设立了一个咨询委员会， 和临床科学家（Andrew Marks、伊拉塔巴斯、Ulrich Jorde、Yoshifuma纳卡、金哲真博士）， 管理员（杰米·鲁宾博士）将提供科学和职业建议。这个问题的核心假设是 应用是，共同的基因表达模式和代谢紊乱决定了结构和 HF患者骨骼肌和心肌的功能变化，这些变化是 通过心室辅助装置放置改善血流动力学后可逆。以前，我有 显示在心力衰竭时骨骼肌局部合成代谢功能受损， 消瘦通过肌肉蛋白水解的激活而发展。我的目标是：1）描述的作用， 泛素-蛋白酶体系统在心力衰竭患者骨骼肌萎缩中的作用 心力衰竭患者萎缩骨骼肌的代谢变化; 3）评估 心室辅助装置对心肌和骨骼肌血流动力学的改善 心力衰竭患者的代谢和蛋白水解。 相关性（参见说明）： 心力衰竭是一种不断扩大的全球流行病，在美国已经影响了500多万人。 运动不耐症和肌肉萎缩是外周代谢受损的结果， 心力衰竭的死亡率本研究旨在了解骨骼肌的基本相互作用 以及心肌代谢和功能，最终目标是发现新的治疗方法， 治疗心力衰竭患者的功能下降。

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.