Biochemical Markers of Progressive Heart Disease

描述（由申请人提供）：心脏对病理性应激的适应性反应是一个复杂的过程，反映了损伤的性质、严重程度和持续时间。这些细胞变化中的许多对心脏的综合性能具有可忽略的影响，然而，一些细胞变化已被证明在调节力产生和松弛方面至关重要，这些特性定义了综合心脏性能。在这项提案中，我们建议开发一种独特的诊断工具，磷蛋白抗体芯片，可用于定义潜在的易处理的改变，在适应不良的心脏，可能适合于靶向治疗。两种互补的方法将被嵌入在这个芯片中，第一个是包括现有的抗体探针，已知的信号转导通路被改变适应不良的心脏病，第二个将是一系列新的磷酸化抗体的发展和列入针对特定的肌节蛋白位点，已被证明具有功能意义的重构肌原纤维制剂。最后，我们将使用来自良好表征的动物模型以及来自临床心力衰竭的人类的组织来验证这种诊断工具。 心力衰竭是西方社会死亡和残疾的主要原因，影响超过500万美国人。这种疾病影响心脏的许多方面，但一个基本的缺陷在于肌肉内的收缩元件水平。肌丝蛋白状态的变化是心脏功能变化的基础。该提案的目标是设计一种诊断工具（蛋白质抗体芯片），该工具将允许基于肌丝蛋白质谱评估疾病状态。此外，该工具还可用于识别导致新疗法的肌肉的潜在易处理特征。

DESCRIPTION (provided by applicant): The adaptational response of the heart to a pathologic stress is a complex process that reflects the nature, severity and duration of the insult. Many of these cellular changes have a negligible impact on the integrated performance of the heart however some have been shown to be critically important in moderating force generation and relaxation, properties that define integrated cardiac performance. In this proposal we propose to develop a unique diagnostic tool, a phosphoprotein antibody chip that can be used to define potentially tractable alterations in the maladaptive heart that might be amenable to targeted therapy. Two complementary approaches will be imbedded in this chip, the first is the inclusion of existing antibody probes that target signaling pathways known to be altered in maladaptive heart disease and the second will be the development and inclusion of a series of novel phosphoantibodies directed against specific sarcomeric protein sites that have been shown to have functional significance in reconstituted myofibrillar preparations. Finally we will validate this diagnostic tool using tissue from well characterized animal models as well as from humans with clinical heart failure. PUBLIC HEALTH RELEVANCE: Heart failure is a leading cause of death and disability in Western society, affecting more than 5 million Americans. The disease affects many aspects of the heart but one fundamental defect resides at the level of the contractile elements within the muscle. Changes in myofilament protein status underlie functional changes in the heart. The goal of this proposal is to design a diagnostic tool (a protein antibody chip) that will allow an assessment of disease status based on the myofilament protein profile. Furthermore, this tool may also be used to identify potentially tractable features of the muscle that lead to novel therapies.