细胞坏死调控神经退行性疾病发生发展的作用机制研究

细胞坏死包括程序性坏死和焦亡，二者在病原体感染、神经退行性疾病及免疫疾病中发挥着重要作用。程序性坏死主要是由TNF受体信号通路中蛋白激酶RIP1、RIP3及假激酶MLKL激活所引起。我们前期发现RIP1/RIP3坏死小体形成功能性β淀粉样纤维，发现该淀粉样纤维具有与神经退行性疾病特有aβ、Tau、synuclein蛋白一样的结构性质，解析了该异源复合物的三维精细结构(Cell，2012；Cell，2018) 。但细胞坏死在神经退行性疾病中的作用机制仍然不清楚。本项目拟进一步运用荧光偏振、免疫组织化学、免疫共沉淀等技术和方法，在SH-SY5Y细胞及APP/PS1和RIP3-/-/APP/PS1模型小鼠中，研究RIP3与阿尔兹海默症（AD）关键蛋白aβ、Tau相互作用的分子机理及调控功能，阐明细胞坏死对神经退行性疾病发生发展的作用机制。

Regulated cell necrosis includes cell programmed necrosis and cell pyroptosis, which play critical roles in many physiological and pathological processes, including infection, autoimmunity diseases, and, neurodegenerative diseases. Cell necroptosis is triggered by the kinases RIP1, RIP3, and its downstream pseudokinase MLKL. Our previous work showed that the necrosome RIP1/RIP3 forms a functional amyloid complex, which shares a similar molecular structure with the aβ, Tau, or synuclein protein involved in neurodegenerative diseases (Cell 2012 & Cell 2018). However, the regulatory mechanism of cell necrosis in Alzheimer’s disease keeps unknown. In this proposal, we will carry out the functional studies for the interaction between RIP3 and aβ, Tau proteins in SH-SY5Y cell line and APP/PS1, RIP3-/-APP/PS1 mice models using FRET, immunochemistry and co-immunoprecipitation methods, eventually benefiting our understanding for the molecular mechanism of cell necrosis, and cross-talk relationship between necrosis and neurodegenerative diseases.