Integrated Mechanisms of Cardiac Maladaptation

心脏适应不良的综合机制

• 批准号: 6905904
• 负责人: R John Solaro
• 金额: $ 227.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905904
• 关键词: cardiac myocytes; muscle function; myocardium disorder

DESCRIPTION (provided by applicant): Experiments proposed here continue highly interactive and synergistic interactions among four projects supported by three cores. The projects and cores are linked by a central theme of experiments, which test the hypothesis that sarcomeric remodeling is a critical determinant of the transition from compensated hypertrophy to decompensation and symptomatic heart failure. We broadly define sarcomeric remodeling as post-translational modifications, shifts in isoform population, and shuttling of sarcomeric associated proteins to other signaling pathways. Project 1 (R. John Solaro) is "Molecular Signaling in Cardiac Sarcomeres"; Project 2 (Brenda Russell) is" Mechanical Activity and Myocyte Remodeling ", which tests the hypothesis that the remodeling responses are regulated by the strength of mechanical stimuli and the intervals between them. Project 3 (Peter Buttrick) is " Sarcomeric Modifications and Progressive Cardiac Maladaptation", and Project 4 (Pieter de Tombe) is "Molecular Mechanisms of Myofilament Dysfunction in Heart Failure", which tests the hypothesis that up-regulation of protein kinase C and specific phosphorylation of sarcomeric targets leads to decompensation. These 4 projects are supported by Administrative, Animal, and Analytical Biochemistry Cores. Approaches include structural, mechanical and proteomic approaches in studies of normal and failing preparations at the level of proteins, single myofibrils, cells, muscles, and hearts. Data from these experiments provide novel insights into the mechanisms of heart failure and potential therapies.

描述（由申请人提供）： 这里提出的实验继续在三个核心支持的四个项目之间进行高度互动和协同的互动。这些项目和核心通过实验的中心主题联系起来，这些实验检验了这样的假设：肌节重塑是从代偿性肥大向失代偿和症状性心力衰竭转变的关键决定因素。我们将肌节重塑广泛地定义为翻译后修饰、异构体群体的转变以及肌节相关蛋白向其他信号通路的穿梭。项目 1（R. John Solaro）是“心脏肌节的分子信号传导”；项目2（Brenda Russell）是“机械活动和肌细胞重塑”，它测试了重塑反应受机械刺激强度及其间隔时间调节的假设。项目 3 (Peter Buttrick) 是“肌节修饰和进行性心脏适应不良”，项目 4 (Pieter de Tombe) 是“心力衰竭中肌丝功能障碍的分子机制”，该项目检验了蛋白激酶 C 上调和肌节靶点特异性磷酸化导致失代偿的假设。这 4 个项目得到行政、动物和分析生物化学核心的支持。方法包括在蛋白质、单个肌原纤维、细胞、肌肉和心脏水平上研究正常和失败制剂的结构、机械和蛋白质组学方法。这些实验的数据为心力衰竭的机制和潜在的治疗提供了新的见解。