RIPK3/MLKL介导细胞程序性坏死的分子机制及其在肠道炎症中的作用机理研究

细胞坏死在过去长时期被认为是一种非程序性细胞死亡，但最近研究发现细胞坏死是受到基因调控的程序性死亡，其中RIPK3、RIPK1、FADD、MLKL、CASPASE8等基因是细胞坏死信号通路调节的关键分子，同时细胞程序性坏死还参与调控多种疾病的发生发展，但目前对细胞程序性坏死的具体分子机制以及在相关疾病中的作用机理并不十分清楚。我们之前通过小鼠模型研究发现FADD通过抑制Caspase8的激活，进而抑制RIPK1蛋白的剪切，从而阻断细胞坏死通路的进行。本项目拟利用体外细胞水平诱导细胞不同死亡形式的模型深入研究RIPK3、MLKL在介导细胞程序性坏死信号传导过程中的分子机制，同时利用基因敲除小鼠遗传手段结合分子生物学与细胞生物学技术，深入研究细胞程序性坏死在胚胎发育及免疫细胞发育和功能，以及在肠道炎症中的作用机理，阐明关键分子的功能和作用机制，为炎症疾病的治疗提供新的策略和思路。

Necrosis has been traditional considered as an unregulated cell death. However, growing evidence has indicated that a subset of necrosis, known as necroptosis, is also highly regulated by intrinsically defined mechanisms. In the recent studies, a signaling complex called necrosome, which contains RIPK3、RIPK1、FADD, has been revealed as key signaling factors in the necroptosis. Although the necroptosis has been implicated in the pathology of a number disease, the signaling events that lead to necroptosis and connection between related disease and necroptosis are still largely unknown. In our previous studies, we have shown that the activation of caspase-8 depends on the adaptor molecule FADD results the RIPK1 cleavage, which required for necroptosis. The deletion of RIPK1 gene rescues the embryonic lethality of FADD knockout mice. In order to exploring the molecular mechanism and functional significance of RIPK3、MLKL on necroptosis, we plan to combine molecular cell biological method and genetic method to address the mechanism of gene interaction in necroptosis by utility of knockout mice. We will study the molecular signals that necroptosis collaborating with apoptosis regulate IECs and evaluate how it impacts on the control intestinal inflammation by using necroptosis-related genes deficient mouse resulting in spontaneous intestinal inflammation model. These studies will allow us to unravel the new mechanism of necroptosis signaling and better understand the signals that maintenance of intestinal mucosal immune homeostasis and to develop strategies to control it in physiological and pathological conditions. The ultimate goal of our research is to develop potential therapeutic strategy for necroptosis related disease.