Myofilament Function in Human Heart Failure

人类心力衰竭中的肌丝功能

• 批准号: 6930069
• 负责人: Peter N. Buttrick
• 金额: $ 47.92万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930069
• 关键词: cardiovascular disorder epidemiology; clinical research; cytoskeletal proteins; heart failure; heart function; human subject; microfilaments; myosins; patient oriented research; phosphorylation; posttranslational modifications; protein isoforms; protein localization; protein structure function; recombinant proteins; sarcomeres; troponin

DESCRIPTION (provided by applicant): The central hypothesis that underlies this project is that the progressive decline in cardiac function seen in patients with non-ischemic heart failure is a reflection of the post-translational modification of cardiac contractile proteins, specifically the thin filaments proteins, troponin I, T and the regulatory myosin light chain (MLC2). To test this hypothesis, we will collect myocardial samples from two distinct groups: i) patients with and without diabetes undergoing coronary bypass surgery, ii) patients with idopathic dilated cardiomyopathy undergoing cardiac surgery (either ventricular modification or tranplantation) and, as controls patients with normal ventricular function undergoing valve replacement or bypass surgery. We will test the extent of myofilament dysfunction in skinned cells and determine whether dephosphorylation by PP1A will eliminate differences between sample groups (aim 1). Next, we will correlate myofilament function and clinical status with contractile protein isoform distribution and phosphorylation status, paying particular attention to the components of the troponin complex and the regulatory myosin light chain (aim 2). Finally, sarcomeric proteins will be extracted in the context of the pathologic cell and replaced with recombinant proteins that have been modified so as to recapitulate the non-pathologic situation (aim 3). The overall goal of the project is to identify specific and modifiable biochemical interfaces that might allow rational treatment of nonischemic cardiac muscle dysfunction.

描述（由申请人提供）：该项目基础的中心假设是，非缺血性心力衰竭患者的心脏功能逐渐下降是对心脏收缩蛋白的翻译后修饰的反映，具体是薄细丝蛋白，肌蛋白I，T和调节性肌动蛋白轻链（MLC）。为了检验这一假设，我们将收集两个不同组的心肌样本：i）接受冠状动脉搭桥手术的糖尿病患者，ii）患有心脏手术的心脏手术（心室改性或曲线plant术）的心脏疾病患者，并且作为正常的经过瓣膜替补术的正常室内功能的患者。我们将测试皮肤细胞中肌丝功能障碍的程度，并确定PP1A的去磷酸化是否会消除样品组之间的差异（AIM 1）。接下来，我们将将肌丝功能和临床状态与收缩蛋白同工型分布和磷酸化状态相关联，特别注意肌钙蛋白复合物和调节性肌球蛋白轻链（AIM 2）。最后，将在病理细胞的背景下提取肉类蛋白，并用已修饰的重组蛋白代替，以概括非病理状况（AIM 3）。该项目的总体目标是确定特定且可修改的生化界面，这可能允许合理治疗非缺血性心肌功能障碍。