Integrated Mechanisms of Cardiac Maladaptation

描述(由申请者提供)：我们的项目致力于研究由心脏压力触发的过程的机制，这些过程是适应性的，抵消了应激源，或者是不适应的，加剧了导致失代偿和心力衰竭的应激源。将这些项目联系在一起的项目的主题是我们的假设，即心脏肌节和胞囊水平的变化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转变。该计划有四个高度互动和协同的项目，接近我们的假设，它们的观点和方法相互补充和加强 其他的。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它们的活动，以确保这些方法之间的协同作用和凝聚力。项目1(Solaro)的目标强调通过AMPK/PACI(强调家族性肥厚型心肌病(FHC)的进化和抢救；通过PKCE，以及扩张型心肌病、新的磷酸化位点和抢救)响应代谢信号激活而改变肌节蛋白功能的磷酸化蛋白分析和分子机制。在项目2(Russell/Samarel)中，总体目标是验证这样的假设，即机械应变通过磷酸化粘着斑激酶导致肌动蛋白被CAPZ封顶来调节细胞的延长。在项目3(Lewandoski)中，总体目标是阐明肌丝修饰诱导代谢表型改变的可能性和程度，并阐明代谢途径中适应性和/或心脏保护性转变；在项目4(De Tombe)中，主要目标是在压力或容量超负荷继发的充血性心力衰竭(CHF)模型中确定肌节蛋白磷酸化和肌丝功能在充血性心力衰竭(CHF)发生中的结构-功能关系。实现这些目标的方法包括新的动物模型、用核磁共振测定心脏血流动力学和新陈代谢、心脏、心肌细胞和肌原纤维水平的力学研究、蛋白质组学和蛋白质水平的分子研究。这些方法直接关系到将项目中的结果转化为诊断的目标，并与家族性和获得性心肌病和心力衰竭新疗法的开发直接相关。 家族性和获得性心力衰竭是最常见的心脏疾病之一，是美国大多数住院患者的原因。这里提出的研究提供了在疾病进展的早期进行新的诊断程序的可能性，并为新的治疗方法提供了靶点。(摘要结束)

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)