Integrated Mechanisms of Cardiac Maladaptation

描述（由申请人提供）：我们的计划项目解决了由心脏上的压力触发的过程的机制，这些压力是适应性的并抵消压力源，或者是适应不良的并加剧压力源，导致失代偿和心力衰竭。将这些项目联系在一起的项目的主题是我们的假设，即心脏肌节和肋节水平的改变是这些过程中的主要和关键机制，以及从适应到适应不良的过渡。该计划有四个高度互动和协同的项目接近我们的假设与观点和方法，补充和加强每个 其他.行政，动物和蛋白质组学/分析生物化学核心支持这些项目，并协调其活动，以确保这些方法之间的协同作用和凝聚力。项目1（Solaro）的目的强调磷酸蛋白分析和肌节蛋白功能改变的分子机制，以响应通过AMPK/Paki（重点是家族性肥厚型心肌病（FHC）的演变和拯救）和通过PKCe（重点是扩张型心肌病，新的磷酸化位点和拯救）的代谢信号激活。在项目2（Russell/Samarel）中，总体目标是检验以下假设：机械应变通过肋节处的粘着斑激酶的磷酸化调节细胞延长，导致CapZ对肌动蛋白加帽。项目3（LewandoskI），总体目标是阐明肌丝修饰诱导代谢表型变化的潜力和程度，并阐明代谢途径中的适应性和/或心脏保护性转变，项目4（de Tombe）的主要目的是确定在充血性心力衰竭（CHF）的发展中肌节蛋白磷酸化和肌丝功能的结构-功能关系在豚鼠继发于压力或容量超负荷的CHF的成熟模型中。实现这些目标的方法包括新的动物模型，用NMR测定心脏血流动力学和代谢，在心脏、肌细胞和肌原纤维水平上的机械研究，蛋白质组学和在蛋白质水平上的分子研究。这些方法直接关系到将项目中的发现转化为诊断的目标，以及家族性和获得性心肌病和心力衰竭的新疗法的开发。 家族性和获得性心力衰竭是最常见的心脏疾病之一，是美国大部分住院患者的原因。本文提出的研究提供了在疾病进展早期进行新诊断程序的可能性，以及新疗法的靶点。(End摘要）

DESCRIPTION (provided by applicant): Our program project addresses the mechanisms of processes triggered by stresses on the heart that are adaptive and offset the stressor or are maladaptive and exacerbate the stressor leading to decompensation and heart failure. The theme of the program that ties the projects together is our hypothesis that alterations at the level of cardiac sarcomeres and costameres are primary and critical mechanisms in these processes and the transition from adaptation to maladaptatlon. The program has four highly interactive and synergistic projects approaching our hypothesis with perspectives and approaches that complement and reinforce each other. Administrative, Animal, and Proteomics/ Analytical Biochemistry Cores support these projects and coordinate their activities to ensure synergy and cohesion among these approaches. Objectives of Project 1 (Solaro) emphasize phospho-protein analysis and molecular mechanisms of altered sarcomeric protein function in response to metabolic signaling activation via AMPK/Paki (with emphasis on the evolution and rescue of familial hypertrophic cardiomyopathy (FHC); and via PKCe, and with emphasis on dilated cardiomyopathy, novel phosphorylation sites and on rescue. In Project 2 (Russell/Samarel) the overall objective is to test the hypothesis that mechanical strain regulates cell lengthening by phosphorylation of focal adhesion kinase at the costamere leading to actin capping by CapZ. In Project 3 (LewandoskI), the overall objective is to elucidate the potential for, and the extent to which myofilament modifications induce changes in metabolic phenotype and elucidate adaptive and/or cardioprotective shifts in metabolic pathways, In Project 4 (de Tombe) the major objective is to determine the structure-function relations of sarcomeric protein phosphorylation and myofilament function in the development of congestive heart failure (CHF) in a well-established model of CHF in the guinea-pig secondary to pressure- or volume overload. Approaches to these objectives include novel animal models, determination of cardiac hemodynamics and metabolism with NMR, mechanical studies at the level of the heart, myocytes, and myofibrils, proteomics, and molecular studies at the protein level. The approaches are directly related to the goal of translating findings in the projects to the diagnosis and to the development of novel therapies in familial and acquired cardiomyopathies and heart failure. Familial and acquired heart failure are among the most prevalent disorders of the heart and responsible for the majority of hospital admissions in the USA. Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract)