Biochemical Markers of Progressive Heart Disease

描述(申请人提供)：心脏对病理性压力的适应性反应是一个复杂的过程，反映了侮辱的性质、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的影响可以忽略不计，然而一些已经被证明在调节力量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，一种磷蛋白抗体芯片，可以用来定义可能适合靶向治疗的适应不良心脏中潜在的易处理的变化。该芯片将嵌入两种互补的方法，第一种是包含现有的抗体探针，这些抗体探针针对已知的在不适应性心脏病中改变的信号通路；第二种是开发和包含一系列针对特定肌节蛋白位点的新型磷酸抗体，这些抗体已被证明在重组肌纤维制剂中具有功能意义。最后，我们将使用具有良好特征的动物模型以及患有临床心力衰竭的人类的组织来验证该诊断工具。 公共卫生相关性：在西方社会，心力衰竭是导致死亡和残疾的主要原因，影响着500多万美国人。这种疾病影响心脏的许多方面，但一个根本的缺陷存在于肌肉内收缩元素的水平上。肌丝蛋白状态的变化是心脏功能变化的基础。这项提议的目标是设计一种诊断工具(蛋白质抗体芯片)，允许根据肌丝蛋白图谱评估疾病状态。此外，这个工具还可以用来识别肌肉的潜在易处理特征，从而导致新的治疗方法。

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.