Biochemical Markers of Progressive Heart Disease

进行性心脏病的生化标志物

• 批准号: 8247680
• 负责人: Peter N. Buttrick
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247680
• 关键词: Adrenergic beta-Antagonists; Affect; American; Animal Model; Antibodies; Biochemical; Biochemical Markers; Biopsy; Calcium; Cardiac; Cause of Death; Clinical; Complex; Contractile Proteins; Defect; Depressed mood; Development; Diagnostic; Disease; Elements; Functional disorder; Generations; Genetic Transcription; Goals; Grant; Heart; Heart Diseases; Heart Transplantation; Heart failure; Human; Implantable Defibrillators; In Situ; Individual; Laboratories; Lead; Link; Microfilaments; Muscle; Muscle Cells; Myocardium; Nature; Pathologic; Patients; Pattern; Performance; Phosphoproteins; Phosphorylation; Post-Translational Protein Processing; Preparation; Process; Property; Protein Microchips; Proteins; Relaxation; Research Personnel; Role; Series; Severities; Signal Pathway; Signal Transduction Pathway; Site; Societies; Staging; Stress; Time; Tissue Sample; Tissues; Translations; Troponin I; Troponin T; Work; base; design; disability; human subject; myosin-binding protein C; novel; protein profiling; public health relevance; reconstitution; response; tool

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.

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，反映了侮辱的性质、严重程度和持续时间。许多这些细胞变化对心脏的综合性能的影响可以忽略不计，但有些已被证明在调节力的产生和放松方面至关重要，这些特性定义了心脏的综合性能。在这项建议中，我们建议开发一种独特的诊断工具，一种磷酸蛋白抗体芯片，可用于定义可能适合靶向治疗的不适应心脏中潜在的可处理的改变。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，其目标是已知在适应性不良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肉蛋白位点的新型磷抗体，这些位点已被证明在重建的肌原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临床心力衰竭患者的组织来验证这一诊断工具。