Role of Programmed Necrosis in Immune Responses

描述（由申请人提供）：本提案的中心主题是一种新的程序性细胞死亡（PCD）途径（称为“程序性坏死”）的分子和生物学表征。这一建议的重要性突出了大量的证据，说明PCD在许多生物过程中发挥的关键作用，包括发育，癌症，自身免疫性疾病和病毒和细菌感染。与细胞凋亡不同，程序性坏死的特征是细胞膜快速破裂而无染色质凝聚，因此可导致局部组织炎症。由于炎症在触发免疫应答中的重要性，由程序性坏死引起的细胞死亡可能具有普遍的免疫刺激作用。这项拨款申请将研究程序性坏死的分子调控。具体而言，半胱天冬酶和TRAF2在调节程序性坏死中的作用将被检查。该提案的另一个目的是使用牛痘病毒感染作为模型来检查该途径的生物学作用。将测试表达程序性坏死抑制剂的转基因小鼠对牛痘感染的反应。这些实验将提供有关程序性坏死在诱导免疫反应中的作用的重要信息，从这些研究中获得的知识可能有助于开发更好的疫苗。此外，控制细胞死亡可能为治疗自身免疫性疾病提供新的方法。

DESCRIPTION (provided by applicant): The central theme of this proposal is the molecular and biological characterization of a new programmed cell death (PCD) pathway termed "programmed necrosis". The importance of this proposal is highlighted by the abundant evidence illustrating the key roles PCD play in many biological processes including development, cancers, autoimmune diseases and infections by viruses and bacteria. Unlike apoptosis, programmed necrosis is characterized by rapid rupture of the cell membrane without chromatin condensation and therefore can result in local tissue inflammation. Because of the importance of inflammation in triggering an immune response, cell death by programmed necrosis may have a general immuno-stimulatory effect. This grant application will examine the molecular regulation of programmed necrosis. Specifically, the role of caspases and TRAF2 in regulating programmed necrosis will be examined. Another objective of the proposal is to examine the biological role of this pathway using vaccinia virus infection as a model. Transgenic mice expressing an inhibitor of programmed necrosis will be tested for their response to vaccinia infection. These experiments will provide important information on the role of programmed necrosis in the induction of immune responses, and the knowledge gained from these studies may aid the development of better vaccines. Moreover, controlling cell death may offer a novel approach to treating autoimmune diseases.