炎症因子对FOXP3+调节性T细胞分化与功能的动态影响及其机理研究

项目名称： 炎症因子对FOXP3+调节性T细胞分化与功能的动态影响及其机理研究

项目编号： No.81330072

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 李斌

作者单位： 上海交通大学

项目金额： 290万元

中文摘要： 调节性T细胞(Treg)通过限制免疫系统过度激活来维持自我耐受和免疫稳态。叉头状转录因子家族P3蛋白(FOXP3)是决定Treg分化与功能的主要转录因子,对维持其生理功能至关重要。在病理环境下，炎症因子如何导致FOXP3+Treg分化异常及功能失活，进而导致免疫系统过度激活，其分子机制尚不清楚。.我们先前的研究显示FOXP3通过与众多转录调控蛋白动态结合形成高分子复合体从而行使其在Treg细胞中的功能。本课题将在前期鉴定FOXP3蛋白复合体亚基组分的基础上，研究在生理和病理特别是炎症因子存在下FOXP3复合物成分的动态变化，各组分蛋白翻译后修饰及其活性调节的分子机制。我们将利用新发现的FOXP3复合物组分为指导性靶点，利用中药单分子库筛选出特异性调节FOXP3活性及Treg功能的抑制剂和激动剂，为自身免疫疾病和其他重大免疫疾病包括哮喘，肿瘤诊断和治疗提供新的药物靶点和研究思路。

中文关键词： 调节性T细胞;FOXP3复合物;翻译后修饰;自身免疫疾病;哮喘

英文摘要： Regulatory T cells(Tregs) are indispensable for the maintenance of dominant self tolerance and immune homeostasis. It could suppress the activation, proliferation and effector functions of effector T cells and APCs. Forkhead box P3 (FOXP3) is a master regulatory factor in Tregs, and is necessary for the suppressive function of Tregs. However, it is still unclear how FOXP3 regulates Treg function, especially under different conditions..It becomes evident that the differentiated state of Treg cells is not determined solely by FOXP3. FOXP3 cooperates with its binding partners to form multiple feedback loops to regulate Treg function. In this research, we plan to work on dynamics of FOXP3 complex in the physical and pathological conditions by purifying FOXP3 complex with tandem affinity purification. The molecular mechanisms and signal pathways would be characterized. We also tried to verify the different post-translational modifications of FOXP3 in the different conditions. We would screen Chinese traditional medicines to modulate Treg function according to the new mechanisms we found. Our work would unveil novel mechanisms on Treg regulation and might provide new targets for the therapeutic manipulation of autoimmune diseases and tumors.

英文关键词： Regulatory T cells;FOXP3 complex;posttranslational modification;autoimmune disease;Asthma