Integrated Mechanisms of Cardiac Maladaptation

描述（由申请人提供）： 这里提出的实验继续由三个核心支持的四个项目之间的高度互动和协同作用。这些项目和核心是由一个中心主题的实验，测试的假设，即肌节重塑是一个关键的决定因素，从代偿性肥大的失代偿和症状性心力衰竭的过渡。我们将肌节重塑广义地定义为翻译后修饰、同种型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“心脏肌节中的分子信号传导”;项目2（Brenda Russell）是“机械活动和肌细胞重塑”，该项目测试了重塑反应受机械刺激强度及其之间的间隔调节的假设。项目3（Peter Buttrick）是“Sarcomeric Modifications and Progressive Cardiac Maladaptation”，项目4（Pieter de Tombe）是“Molecular Mechanisms of Myofilament Dysfunction in Heart Failure”，该项目测试了蛋白激酶C的上调和肌节靶点的特异性磷酸化导致失代偿的假设。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.