Integrated Mechanisms of Cardiac Maladaptation

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作用。这些项目和核心通过一个中心实验主题联系在一起，这些实验测试了肌节重塑是从代偿性肥厚过渡到失代偿性和症状性心力衰竭的关键决定因素的假设。我们广泛地将肌节重塑定义为翻译后修饰、异构体群体的改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“心脏肌节中的分子信号”；项目2(Brenda Russell)是“机械活动和心肌细胞重塑”，它测试了重塑反应受机械刺激强度和机械刺激之间的间隔调节的假设。项目3(彼得·巴特里克)是“肌节修饰和进行性心脏适应不良”，项目4(Pieter De Tombe)是“心力衰竭时肌丝功能障碍的分子机制”，它测试了蛋白激酶C上调和肌小节靶标的特异性磷酸化导致失代偿的假说。这4个项目得到了行政、动物和分析生物化学核心的支持。方法包括结构、机械和蛋白质组学方法，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的准备。这些实验的数据为心力衰竭的机制和潜在的治疗方法提供了新的见解。

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.