程序性坏死信号通路调控免疫老化T细胞功能参与衰老相关炎症的研究

项目名称： 程序性坏死信号通路调控免疫老化T细胞功能参与衰老相关炎症的研究

项目编号： No.81471397

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周晓辉

作者单位： 复旦大学

项目金额： 70万元

中文摘要： 衰老相关炎症状态在诸多老年性疾病致病中起关键作用，但其本身发生、维持的分子细胞机制尚不明了,免疫老化T细胞在其中可能发挥重要作用。数据显示，免疫老化T细胞易受刺激而产生多种促炎细胞因子，故可参与衰老相关炎症过程；课题组前期工作发现,程序性坏死（necroptosis）信号通路是调控年轻T细胞功能的重要机制之一；老年CD4+ 及CD8+ T细胞中程序性坏死关键分子RIP3的表达水平显著减少。据此推测，程序性坏死通路在老年T细胞中的变化可能影响其功能。本课题拟运用T细胞体外刺激、过继性转移、流感病毒感染小鼠等方法，利用基因敲除小鼠模型，剖析程序性坏死信号通路是否参与调控老年T细胞的活化、分化、增殖、缩减等功能，特别是促炎细胞因子的分泌。研究旨在阐明程序性坏死信号通路调控免疫老化T细胞功能的可能机制，探讨该调控作用对衰老相关炎症形成的免疫学意义，为寻找相关老年炎性疾病临床治疗的新靶点提供线索。

中文关键词： 衰老相关炎症；免疫老化；T细胞；程序性坏死；信号通路

英文摘要： Age-related inflammation (or so-called inflamm-ageing state) plays a key role in a large number of diseases in the elderly. However, the cellular and molecular mechanisms of origining and maintaining of this inflamm-ageing state is elusive yet. Immunosenescent T cells are prone to produce higher pro-inflammatory cytokiens, which could promote inflammation and contibute to inflamm-ageing state. Our and others' previous study revealed that RIP1 and RIP3 mediated programmed necrosis, i.e. necroptosis, of which the pathway was checked by FADD, was involved in the regulation of T cells' functions, such as acitvation induced cell death (AICD) in the process of proliferation and contraction. Interestingly, our preliminary data showed that the expression level of RIP3, the key molecule of necroptosis, were decreased in the aged CD4+ T and CD8+ T cells, when compared with their young couterparts. Those observations indicated that the alteration of necroptosis pathway might affect the functions of senescent T cells. Thus, this proposal is aimed to explore the possible role of necroptosis in regulating the functions of the immunosenecent T cells, and the related immunological significances on the inflamm-ageing state. By in vitro T cell stimulation assay, ex vivo T cells' adoptive transfer assay and in vivo influenza virus infection in mouse,we will apply the knockout mice of FADD, RIP1, RIP3 or double knockout of FADD and RIP1, and wildtype mice as contorl, to investigate the possibility of necroptosis pathway regulating the aged CD4+ T cells' function, such as activation, differentiation, proliferation and contraction, especially production of the proinflammatory cytokines. Those data might help to understood the relationship between the cell death pathway of necroptosis and the immunosenescent CD4+ T cells' functions, and shed light on a new mechanism which could contribute to the age-related inflammation. Ultimately, new clues could be expected to figure out new targets for effective therapeutic approahces of inflamm-ageing related diseases.

英文关键词： age-related-inflammation;immunosenescence;T cells;necroptosis;signaling pathways