mTOR信号通路对布鲁氏菌侵染小胶质细胞自噬及极化的调控机制

近年来布鲁氏菌病在宁夏一些局部地区呈上升趋势，并发或以脑膜炎为首发的患者不断出现，引起临床医师的关注，因此揭示其脑损害机制，是急需解决的重要问题。综合课题组前期布鲁氏菌的系列研究分析，推测小胶质细胞自噬抑制和M2型极化与布鲁氏菌胞内寄生有关，自噬不足或过度和小胶质细胞M1型过度活化则会造成中枢神经系统损伤，PI3K/AKT/mTOR信号通路在自噬及细胞极化中发挥重要作用。本研究拟通过布鲁氏菌感染小胶质细胞的细胞模型，结合神经型布鲁氏菌病患者脑脊液及外周血液，采用mTOR信号通路抑制剂、自噬诱导剂及抑制剂、蛋白印迹、mTOR-SiRNA等技术，探讨PI3K/AKT/mTOR信号通路在自噬及小胶质细胞极化中的作用及其机制；明确小胶质细胞不同亚型活化及自噬在中枢神经系统的优势诱导和局部富集机制；阐明其介导炎症或杀伤效应的分子与损伤机制；为设计基于细胞自噬及极化亚型的疾病防治新策略提供实验室依据。

Brucellosis in some local areas of Ningxia is on the rise recent years. Patients with complicating or primary meningitis cause the attention of clinicians. Thus revealing the mechanism of brain damage, is one of the important problems need to be solved. According to our preliminary data, we speculate that microglia autophagy inhibition and M2 polarization is associated with intracelluar parasitism. At the same time, Insufficient or enhanced autophagy and over activiated M1 polarization cause brain damage. mTOR signaling pathway has important role with autophagy and polarization. By study proposed by brucella infection cell model of microglia and cerebrospinal fluid and peripheral blood samples of brucella patients, we plan to:1) Explore the role of PI3K/AKT/mTOR signaling pathway in autophagy and microglia polarization, using mTOR signaling pathway inhibitors, autophagy inducer and inhibitor, western blotting and mTOR - SiRNA technology. 2) Clearly delineate the mechanism of subtypes activation of microglial cells, predominance inducing autophagy in the central nervous system and the advantages of induction and local enrichment. 3) Clarify the key molecular and damage mechanism of mediating inflammation or killing effect. The new strategies based on cell autophagy and polarization provide laboratory basis for disease control and prevention.