FOXO1在TNFR-Fc抑制急性肺损伤肺泡上皮细胞凋亡中的机制研究

项目名称： FOXO1在TNFR-Fc抑制急性肺损伤肺泡上皮细胞凋亡中的机制研究

项目编号： No.81200002

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 李理

作者单位： 广州军区广州总医院

项目金额： 23万元

中文摘要： 我们的前期研究发现在LPS诱导ALI小鼠模型中以TNFR-Fc中和过度表达的TNF-α能显著减轻肺组织细胞凋亡，同时伴随MAPK活性下调 ，Bcl2/Bax基因表达比值上调。既往的研究表明FOXO1参与了组织细胞的凋亡/增殖调控过程。我们推测，FOXO1可能是TNFR-Fc中和过量的TNF-α、减轻肺组织细胞凋亡调控的关键节点。鉴此，本课题通过激酶分析、基因芯片、生物信息学、RNA干扰等方法，研究TNFR-Fc干预后，FOXO1活化、FOXO1对凋亡相关基因的转录调控及对细胞凋亡的影响，探讨TNFR-Fc中和TNF-α，打破ALI炎症/氧化放大环路过程中，FOXO1在调控细胞凋亡/增殖中的作用机制，从细胞凋亡/增殖的角度诠释TNF-α中和减轻肺组织结构损伤ALI治疗策略，为TNFR-Fc治疗 ALI 提供更充分的临床前期实验依据，为保护肺结构细胞的干预靶点药物研发奠定理论及实验基础。

中文关键词： FOXO1；肿瘤坏死因子受体-抗体融合蛋白；急性肺损伤；肺泡上皮细胞；细胞凋亡

英文摘要： Our previous study showed that TNFR-Fc attenuated lung injury and cell apoptosis in ALI mice induced by LPS via TNF-α blockade, accomany with downregulating the expression of MAPK and the ratios of Bax/Bcl-2 gene. FOXO1 is important in the process of apoptosis and proliferation. We hypotheses that FOXO1 was the key transcription factor in the signal transduction pathway following TNF-α blockade. However the mechanism of FOXO1 enrolling in attenuating the apoptosis of alveolar epithelial cell is unclear. To achieve the potential therapeutic value of TNFR-Fc in ALI, we are going to explore the effect of FOXO1 in ALI mice treated with TNFR-Fc. The composite methods, including kinase assays, gene chips, bioinformatics methods and RNA interference, are to be key steps in our study. We will check several valuable profiles such as FOXO1 activation, gene transcription regulated by FOXO1, interaction between FOXO1 and NF-κB after TNFR-Fc administration in ALI mice. Promisingly, we can elucidate the anti-apoptosis mechanism of TNFR-Fc in attenuating lung injury of ALI mice via FOXO1.

英文关键词： FOXO1；TNFR-Fc；Acute lung injury；alveolar epithelial cell；apoptosis