Cardiac and Skeletal Muscle Metabolism and Proteolysis in Heart Failure

这份建议详细说明了我在学术领域的职业发展的5年全面培训计划。 心血管内科。在哥伦比亚大学完成心血管内科临床培训后 大学医学中心，我计划开始一个有指导的研究计划，提供额外的科学研究 独立从事生物医学研究所需的培训。我将在以下方面获得深入的经验 细胞生物学、遗传学、分子生物化学、新陈代谢和活体生理学 慢性心力衰竭患者的代谢紊乱和运动耐量。唐娜博士 曼奇尼和艾拉·戈德堡将指导我的科学和职业发展。曼奇尼博士是一位国际性的 在心力衰竭和移植、运动生理学和新陈代谢领域的公认领导者 心血管疾病，并在学术上有成功的职业指导记录 医学和基础科学。艾拉·戈德伯格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，成立了基础心血管咨询委员会 和临床科学家(Andrew Marks博士、Ira Tabas博士、Ulrich Jorde博士、Yoshiuma Naka博士、金哲珍博士)和 管理人员(杰米·鲁宾博士)将提供科学和职业建议。这一点的中心假设是 应用是常见的基因表达模式和代谢紊乱决定结构和 心衰患者骨骼肌和心肌的功能变化 放置脑室辅助装置后血流动力学改善是可逆的。在此之前，我已经 表明在心力衰竭和进行性肌肉中骨骼肌的局部合成代谢功能受到损害 消瘦是通过激活肌肉蛋白分解来实现的。我的目标是：1)描述 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)评估心力衰竭对骨骼肌萎缩的影响 心肌和骨骼肌放置脑室辅助装置后血流动力学的改善 心力衰竭患者的代谢和蛋白分解。 相关性(请参阅说明)： 心力衰竭是一种在全球范围内蔓延的流行病，已经影响到美国500多万人。 运动不耐受和肌肉萎缩是由外周新陈代谢受损引起的，是 心力衰竭的死亡率。这项研究旨在了解骨骼肌的基本相互作用。 和心肌代谢和功能，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衰退。

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.