Caspase8和RIP3调控细胞程序性坏死的关键机制研究

细胞死亡是生物体的基础生命活动，在发育及形态发生、组织稳态、机体免疫防御等生理过程中具有重要作用。细胞程序性坏死是近年发现的重要细胞死亡信号通路。在细胞程序性坏死的信号传导中，RIP3、Caspase8和RIP1等蛋白通过相互结合、修饰激活、剪切及降解等发挥关键作用，目前对这个过程的相关生理病理功能的认识仍不清楚。本项目拟利用已构建的RIP3蛋白RHIM结构域点突变小鼠Rip3V448P/V448P及Caspase8剪切位点D387突变小鼠Caspase8D387A/D387A，结合分子生化、细胞生物学技术手段，系统深入研究RIP3蛋白RHIM结构域及Caspase8剪切调控细胞死亡及炎症反应的作用机制，并通过进一步动物疾病模型及小鼠多基因敲除回复的遗传学手段，阐明其生理病理作用机制，为相关自身免疫性疾病、神经退行性疾病以及肿瘤等疾病的防治提供新的理l论基础

Cell death is intricately connected with life in multicellular organisms. Programmed cell death (PCD) is essential for many physiological processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. Necroptosis is a newly discovered pathway of regulated necrosis that regulated by cleavage, kinase, oligomerization of complex including the proteins Caspase8/RIP1/RIP3. However, the mechanism by which Caspase8, RIP1 and RIP3 regulate necroptosis, apoptosis and inflammation in vivo remain at large. Here, we generated both RIP3 V448P mutant in RHIM domain and Caspase 8 D387A mutant on cleavage site knock-in mice. We will take advantage of these mouse models to explore the mechanisms underline signaling regulated by the cleavage, activation, and oligomerization of complex including the proteins Caspase8/RIP1/RIP3. This project would promote the drug discovery on Caspase8/RIP1/RIP3 specific function, and also contribute to therapeutic intervention of related-diseases.