蛋白激酶RIP1泛素化修饰调控胚胎发育与免疫炎症的机制研究

受体相互作用蛋白激酶1(RIP1)是参与调控细胞凋亡、细胞程序性坏死以及炎症信号通路的关键分子。已有研究证实RIP1的泛素化修饰是决定RIP1介导的信号通路的关键因素，其中人源RIP1的377位点赖氨酸泛素化是RIP1介导NF-κB激活所必需的。但RIP1该泛素化修饰在生理病理条件下如何参与调控不同信号通路还不清楚。本项目拟利用构建的小鼠同源RIP1泛素化376修饰位点赖氨酸突变成精氨酸的点突变小鼠（RIP1K376R）以及RIP1组织特异性点突变小鼠（RIP1Flox/K376R），通过分子细胞实验、动物遗传以及疾病模型等多种技术手段，阐明RIP1的376位泛素化修饰调控不同信号通路的分子机制，及其在胚胎发育和免疫炎症中的作用机理,该项目的开展将促进靶向RIP1功能特异性小分子药物的开发及为相关疾病的治疗提供新的思路和理论支持。

Receptor Interacting Protein Kinase-1(RIP1) is a major mediator of apoptosis as well as necroptosis and inflammatory signaling. Ubiquitination of RIP1 plays a very important role in regulating the activating of RIP1 dependent signaling. Although previous studies have demonstrated that K377 in human RIP1 is critical for NF-κB activation, the mechanisms of K377 mediating distinct signaling in vivo remains unknown. To study the endogenous function of K376 in mouse RIP1, we generated RIP1 K376R knock-in mutant mouse line in whole animal and conditional K376R knock-in mutant mouse line using tissue specific Cre in this project. We will take advantage of these mouse models to explore the mechanisms underline signaling regulated by ubiquitination of RIP1 at K376. This project would promote the drug discovery on RIP1 specific function inhibition, and also contribute to therapeutic intervention of related-disease.