Impacts of sarcomeric protein phosphorylation on ischemic hearts

项目摘要 每年在美国，大约200万人经历了心肌缺血（血液不足 供应给心肌）。缺血性心脏病是心力衰竭的常见原因。目前，约1.6 100万缺血后幸存者患有缺血性心力衰竭，这是一种没有有效治疗的致命疾病。 心脏的主要功能是泵出血液，为身体提供营养和氧气。肌节 蛋白质构成心肌的分子马达，对心脏功能至关重要。修改 在各种生理和疾病中，肌节蛋白在调节心脏功能中起着核心作用。 条件我们实验室的长期目标是了解肌节蛋白的修饰如何影响 缺血时的心脏功能以及随之而来的缺血性心力衰竭。这一努力将导致潜在的新的 致命心脏病的治疗策略或生物标志物。本建议侧重于以下方面之一： 关键的肌节蛋白调节因子，称为心肌肌钙蛋白I（cTnI）。最近，我们发现， 在缺血性心力衰竭患者中， 由遗传性心脏肌肉疾病引起。初步研究表明，一个关键的cTnI 修饰位点保护心脏免受缺血相关的损伤，并在心肌细胞中保持高水平的修饰。 继发缺血性心力衰竭。拟议的研究将解决以下问题：cTnI修饰 保护心脏功能免受缺血相关损伤。有两个具体目标：1）调查 通过cTnI修饰传达的分子和细胞心脏保护机制; 2）测试是否 保护功能是拟建场地所独有的。 拟议的项目具有广泛的影响;它不仅会产生关于心脏功能调节的知识， 和缺血性心脏病，而且还帮助首席研究员在摩根建立强大的研究计划， 州立大学，历史上著名的黑人学院和大学的成员，为了促进 生物医学领域和保健领域的劳动力多样性。

PROJECT SUMMARY Each year in the U.S., approximately 2 million people experienced myocardial ischemia (inadequate blood supply to heart muscle). Ischemic heart disease is a common cause of heart failure. Currently, about 1.6 million post-ischemia survivors live with ischemic heart failure, a deadly condition without effective treatment. The main function of the heart is to pump out blood to supply the body with nutrients and oxygen. Sarcomeric proteins make up the molecular motor of the heart muscle, which are essential for heart function. Modifications on sarcomeric proteins play a central role in regulating heart function in various physiological and diseased conditions. The long-term goal of our lab is to understand how modifications on sarcomeric proteins affect heart function in ischemia and the consequent ischemic heart failure. The effort will lead to potential new therapeutic strategies or biomarkers for the deadly heart diseases. The present proposal focuses on one of the key sarcomeric protein regulators, called cardiac troponin I (cTnI). Recently, we have found that its modifications are significantly altered in the patients with ischemic heart failure as well as the heart failure resulting from genetic heart muscle diseases. The preliminary study has shown that one crucial cTnI modification site protects heart from ischemia-related injury and is kept at a high level of modification in the consequent ischemic heart failure. The proposed study will address the question: how the cTnI modification protects heart function from ischemia-related injury. There are two specific aims: 1) to investigate the molecular and cellular cardioprotective mechanism conveyed by the cTnI modification; 2) to test whether the protective function is unique to the proposed site. The proposed project has broad impacts; it will not only produce knowledge about heart function regulation and ischemic heart disease but also help the principal investigator build strong research program at Morgan State University, a prestigious member of Historically Black Colleges and Universities, in order to promote the workforce diversity in biomedical field and health care.