RIP1 and RIP3 regulation of apoptosis, necrosis, and inflammation

描述（由申请人提供）：程序性坏死是一种受RIP1和RIP3激酶调控的细胞死亡形式。许多细胞应激和宿主防御途径为这种程序性坏死提供细胞，在病毒感染的情况下，消除受感染的细胞对宿主有益；然而，当失调的坏死促进炎症并潜在地驱动一系列疾病状态。目前，RIP1和RIP3激酶调控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项目，以确定坏死的分子基础。为了形成一个全面的图景，我们将(1)表征RIP1和RIP3的上下游信号转导途径，(2)识别新的信号成分，(3)制定治疗干预策略，(4)将这些发现扩展到细胞过度死亡引起的炎症的遗传小鼠模型中。这些研究将有助于我们通过抑制或改变细胞死亡方式来治疗疾病。

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.