Identifying novel components of the cardiac necrotic program

描述（由申请人提供）：细胞通过凋亡或坏死的意外死亡可能是人类心脏病的根本原因。虽然细胞凋亡是一个离散的、严格控制的过程，在生理上是细胞选择性删除所必需的，但坏死是一个不明确的级联事件，导致细胞破裂和炎症。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因子的了解相对较少，尽管这种后期形式的细胞死亡可能在人类心脏病（缺血/再灌注损伤、心力衰竭、糖尿病性心肌病、抗癌药物诱导的心脏毒性等）中起着更重要的作用。我们的长期目标是鉴定和充分表征驱动坏死细胞死亡的分子调节蛋白，以便它们可以靶向治疗成人心脏病。虽然坏死似乎是一个不受调节的过程，但它实际上在线粒体水平上受到高度调节，在线粒体水平上，肿胀和ATP生成的丧失通常是第一个可确定的事件。例如，我们已经表明，线粒体内特定的蛋白质介导的改变在坏死性死亡的开始中起关键作用。因此，我们的中心假设是，坏死实际上是由线粒体依赖的特定分子成分介导/启动的，而不是一个不受控制的非特异性过程。因此，本应用程序的目的是鉴定介导坏死细胞死亡的关键蛋白质，并表征一些已经鉴定的有趣的候选蛋白质。我们采用了一种高度创新的组合方法来识别坏死的分子电路，从生物化学方法到脊椎动物模型的研究。这项研究的基本原理是，一旦确定了介导坏死的关键蛋白质，它们就可以作为治疗一系列人类心脏病的手段。心脏细胞的死亡是人类心脏病的一个潜在原因。提出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质，它们就可以作为治疗心脏病患者的一种手段。

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.