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IL-15/T-bet通过Runx3介导CD4+IELs转化在肠缺血再灌注损伤中的作用及机制研究

批准号81500405 学科分类消化道内环境紊乱、黏膜屏障障碍及相关疾病 ( H0306 )
项目负责人邱远 负责人职称讲师 依托单位中国人民解放军第三军医大学
资助金额18.00
万元
项目类别青年科学基金项目 研究期限2016 年 01 月 01 日 至
2018 年 12 月 31 日
中文主题词肠黏膜屏障;缺血再灌注;上皮间淋巴细胞;白介素15;细胞毒性
英文主题词intestinal mucosal barrier;ischemia/reperfusion;intraepithelial lymphocytes;interleukin-15;cytotoxicity

摘要

中文摘要 免疫介导的损伤是肠黏膜屏障损伤的重要环节。IL-15/T-bet信号通路对上皮间淋巴细胞(IELs)的调控是肠免疫系统发挥作用的关键。我们前期发现,肠缺血再灌注(I/R)后IL-15增多,CD4+IELs数量增加、活化增强,参与对肠黏膜屏障破坏。但IL-15通过何种机制调控 CD4+IELs参与该过程尚不清楚。新近研究表明, Runx3决定CD4+IELs向ThPOK-Runx3+细胞毒性T细胞的转化,我们也观察到I/R后CD4+IELs细胞毒性显著增强。因此,我们推测:I/R后IL-15通过激活T-bet,以Runx3依赖的方式,介导CD4+IELs细胞毒作用对黏膜屏障的破坏。为此,本研究拟采用体内外研究模型,通过IL-15刺激或抗体中和,利用流式等技术,阐明IL-15/T-bet与Runx3的作用关系,研究该通路对CD4+IELs转化的影响,为肠黏膜的损伤防治提供新思路。
英文摘要 Immune-mediated injury is a quite important step during intestinal ischemia/reperfusion injury. Activation of T-bet by the IL-15 is involved in intraepithelial lymphocytes (IELs) development and intestinal immune responses. In our previous study, intestinal I/R signicantly increased IL-15 expression and CD4+ IELs subpopulations, and enhanced activation of CD4+ IELs, which is involved in intestinal barrier disruption. However, the mechanism of IL-15 in CD4+ IELs modulation is still unknown. A recent study found Runx3 to be involved in the differentiation of naive CD4+ IELs into ThPOK−Runx3+ CTLs in the gut. We also observed that these cells exhibited high cytolytic activity after I/R. Therefore, we hypothesized that IL-15/T-bet-induced CD4+ IELs cytolytic activity would damage the intestinal barrier via a Runx3-dependent mechanism. In this study, we investigate the relationship between IL-15/T-bet and Runx3 in vitro and in vivo models. Various experimental methods including antibody neutralization and flow cytometry will be used to elucidate the effect of IL-15/T-bet-Runx3 pathway on CD4+ IELs transformation in intestinal I/R. These findings provide profound insight for the development of therapies to prevent and/or treat intestinal I/R injury.
结题摘要

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