Integrated Mechanisms of Cardiac Maladaptation

心脏适应不良的综合机制

• 批准号: 7850180
• 负责人: R John Solaro
• 金额: $ 241.82万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850180
• 关键词: Integrated; Mechanisms; Cardiac; Maladaptation

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)

描述（由申请人提供）：我们的项目研究了由心脏压力引发的过程机制，这些过程是适应性的并抵消压力源，或者是适应不良并加剧压力源，导致失代偿和心力衰竭。将这些项目联系在一起的计划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以及从适应到适应不良的转变中的主要和关键机制。该计划有四个高度互动和协同的项目，以补充和加强每个项目的观点和方法来接近我们的假设 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) 的目标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 的代谢信号激活（重点是家族性肥厚型心肌病 (FHC) 的演变和挽救；以及通过 PKCe，重点是扩张型心肌病、新的磷酸化位点等 救援。在项目 2 (Russell/Samarel) 中，总体目标是测试机械应变通过肋缘粘着斑激酶磷酸化导致 CapZ 封盖肌动蛋白来调节细胞延长的假设。在项目 3 (LewandoskI) 中，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，并阐明适应性 项目 4 (de Tombe) 的主要目标是确定豚鼠继发于压力或容量超负荷的充血性心力衰竭 (CHF) 发展过程中肌节蛋白磷酸化和肌丝功能的结构-功能关系。实现这些目标的方法包括新颖的动物模型、心脏血流动力学的测定和 核磁共振代谢、心脏、肌细胞和肌原纤维水平的机械研究、蛋白质组学和蛋白质水平的分子研究。这些方法与将项目中的发现转化为诊断以及家族性和获得性心肌病和心力衰竭新疗法的开发的目标直接相关。 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。这里提出的研究为疾病进展早期的新诊断程序提供了潜力，并为新疗法提供了目标。 （摘要完）