Identifying novel components of the cardiac necrotic program

识别心脏坏死程序的新组成部分

• 批准号: 7447156
• 负责人: Christopher P Baines
• 金额: $ 4.35万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2008-11-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447156
• 关键词: Adenoviruses; Adult; Animal Model; Antineoplastic Agents; Apoptosis; Binding Proteins; Biochemical; Biological Assay; Candidate Disease Gene; Cardiac; Cardiotoxicity; Cell Death; Cell model; Cells; Cessation of life; Cicatrix; Cultured Cells; Development; Drosophila genus; Event; Generations; Goals; Heart Diseases; Heart failure; Human; Hybrids; Inflammation; Ischemia; Lead; Mediating; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Muscular Dystrophies; Necrosis; Numbers; Patients; Play; Process; Proteins; Proteomics; Public Health; RNA Interference; Range; Reperfusion Injury; Research; Role; Rupture; Screening procedure; Swelling; Testing; Tissues; Vertebrates; Yeasts; combinatorial; cyclophilin D; diabetic cardiomyopathy; genetic regulatory protein; heart cell; innovation; interest; mitochondrial dysfunction; novel; programs; research study; response

DESCRIPTION (provided by applicant): The unwanted death of cells through apoptosis or necrosis can be a fundamental cause of cardiac disease in humans. Although apoptosis is a discrete, tightly controlled process that is physiologically necessary for the select deletion of cells, necrosis is an ill-defined cascade of events that leads to cell rupture and inflammation. While the molecular mechanisms that promote apoptosis have been extensively defined, relatively little is understood of the molecular regulators of necrosis, despite the fact that this later form of cell death likely plays a much more prominent role in human cardiac disease (ischemic/reperfusion injury, heart failure, diabetic cardiomyopathy, anti-cancer agent-induced cardiotoxicity, etc.). Our long-range goal is to identify and fully characterize the molecular regulatory proteins that drive necrotic cell death so that they can be targeted for the treatment of adult cardiac disease. While necrosis can appear to be an unregulated process, it is actually highly regulated at the level of the mitochondria where swelling and loss of ATP generation are often the first definable events. For example, we have shown that specific, protein-mediated alterations within mitochondria function as critical events in the initiation of necrotic death. Thus, our central hypothesis is that, rather than being an uncontrolled, non-specific process, necrosis is in fact mediated/initiated by specific molecular components that are mitochondrial-dependent. The objective of the present application, therefore, is aimed at identifying critical proteins that mediate necrotic cell death, and to characterize a number of interesting candidate proteins that have already been identified. We have employed a highly innovative, combinatorial approach to identify the molecular circuitry of necrosis that ranges from biochemical approaches to studies in vertebrate animal models. The rationale for the proposed research is that once key proteins that mediate necrosis are identified, they can be targeted as a means of treating a whole array of human cardiac diseases. PUBLIC HEALTH RELEVANCE The death of heart cells is an underlying cause of human heart disease. The proposed research is aimed at uncovering the molecular mechanisms that lead to heart cell death. Once the key proteins that mediate cell death are identified, they can then be targeted as a means of treating patients with heart disease.

描述(由申请人提供)：细胞通过凋亡或坏死而不受欢迎的死亡可能是人类心脏病的根本原因。尽管细胞凋亡是一个离散的、严格控制的过程，在生理上是选择性删除细胞所必需的，但坏死是一系列导致细胞破裂和炎症的模糊事件。虽然促进细胞凋亡的分子机制已被广泛定义，但对坏死的分子调节机制了解相对较少，尽管这种后一种形式的细胞死亡可能在人类心脏疾病(缺血/再灌注损伤、心力衰竭、糖尿病心肌病、抗癌剂诱导的心脏毒性等)中发挥更突出的作用。我们的长期目标是识别和充分表征导致坏死细胞死亡的分子调控蛋白，以便将它们作为治疗成人心脏病的靶点。虽然坏死看起来可能是一个不受调控的过程，但实际上它在线粒体水平上受到高度调控，在线粒体水平上，肿胀和ATP生成的丧失往往是第一个可定义的事件。例如，我们已经证明，线粒体内特定的、蛋白质介导的改变在坏死性死亡的启动中起关键作用。因此，我们的中心假设是，坏死不是一个不受控制的、非特异性的过程，而是实际上是由线粒体依赖的特定分子成分介导/启动的。因此，本申请的目的是鉴定介导坏死性细胞死亡的关键蛋白质，并鉴定已经鉴定的一些有趣的候选蛋白质。我们采用了一种高度创新的组合方法来识别坏死的分子回路，范围从生化方法到脊椎动物模型的研究。这项拟议研究的基本原理是，一旦确定了介导坏死的关键蛋白，它们就可以作为治疗一系列人类心脏病的一种手段。公共卫生相关性心脏细胞的死亡是人类心脏病的根本原因。这项拟议的研究旨在揭示导致心脏细胞死亡的分子机制。一旦确定了介导细胞死亡的关键蛋白，它们就可以作为治疗心脏病患者的一种手段。