RIP1 and RIP3 regulation of apoptosis, necrosis, and inflammation

描述(由申请人提供)：程序性坏死是一种由RIP1和RIP3激酶指导的调节形式的细胞死亡。许多细胞应激和宿主防御途径为这种程序性坏死的细胞提供了基础，在病毒感染的背景下，感染细胞的消除有利于宿主；然而，当失调的坏死促进炎症并可能驱动一系列疾病状态时。目前，RIP1和RIP3激酶控制的信号网络尚不清楚。美国国立卫生研究院院长的早期独立奖将使我能够建立一个研究计划，以确定坏死的分子基础。为了生成一个全面的图像，我们将(1)描述RIP1和RIP3上游和下游的信号转导通路，(2)确定新的信号组件，(3)开发治疗干预策略，(4)将这些发现扩展到过度细胞死亡引起的炎症的遗传小鼠模型。这些研究将有助于我们通过抑制或改变细胞死亡模式来治疗疾病。 公共卫生相关性：目前的项目重点是确定RIP1和RIP3激酶在激活死亡受体和病原体识别受体通路后的炎症和程序性细胞死亡中的作用。这些激酶的失调引起的疾病以及病原体的颠覆策略将被研究。更明确地理解RIP激酶在宿主防御和控制细胞命运中的作用，将产生调节坏死细胞死亡的新疗法的设计。

DESCRIPTION (provided by applicant): Programmed necrosis is a regulated form of cell death directed by the kinases RIP1 and RIP3. A number of cell stress and host defense pathways prime cells for this programmed necrosis, and in the context of viral infection, elimination of infected cells benefits the host; however, when dysregulated necrosis promotes inflammation and potentially drives a range of disease states. At present, the signaling networks control by RIP1 and RIP3 kinases remain unclear. The NIH Director's Early Independence Award will enable me to establish a research program to define the molecular basis of necrosis. To generate a comprehensive picture, we will (1) characterize the signal transduction pathways upstream and downstream of RIP1 and RIP3, (2) identify new signaling components, (3) develop strategies for therapeutic intervention, and (4) extend these finding to genetic mouse models of inflammation caused by excessive cell death. These studies will contribute to our ability to treat disease through suppressing or altering cell death modalities. PUBLIC HEALTH RELEVANCE: The current project focuses on defining the role of RIP1 and RIP3 kinases in inflammation and programmed cell death following activation of death receptor and pathogen recognition receptor pathways. Disease caused by dysregulation of these kinases as well as pathogen subversion strategies will be examined. The design of novel therapies to modulate necrotic cell death will emerge from a more defined understanding of RIP kinases in host defence and in controlling cell fate.