肠道菌群代谢产物格拉司琼上调Indian Hedgehog减轻肠缺血再灌注损伤的作用及机制

批准号:
82002088
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
闫征征
依托单位:
学科分类:
器官功能衰竭与支持
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
闫征征
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中文摘要
肠缺血再灌注(I/R)导致肠损伤,是围术期患者死亡的原因之一。肠损伤过程中巨噬细胞可释放Hedgehog(Hh)信号通路配体Indian Hedgehog(Ihh)激活肠道干细胞,修复肠损伤,但机制不明。研究表明STAT1缺失可促进Runx2的核转位,增加Ihh的表达,促进细胞增殖,但在肠I/R损伤中是否存在此通路仍未知。我们预实验发现肠道菌群代谢产物格拉司琼(GA)可抑制肠I/R引起的五羟色胺受体3(5-HT3R)表达上调,促进Ihh的表达,提高小鼠的存活率。GA如何调节Ihh的表达及其在肠I/R中的作用尚无报道。据此推测:肠I/R时,菌群产生的GA抑制肠I/R诱导的STAT1活化,促进Runx2核转位,启动Ihh的转录表达,进而修复肠损伤。本项目拟采用5-HT3R及Ihh基因敲除小鼠和小肠类器官离体模型,研究GA及Ihh在肠I/R损伤中的作用及机制,为临床防治肠I/R损伤提供理论依据。
英文摘要
Intestinal ischemia-reperfusion (I/R) is one of the causes of perioperative death. During intestinal injury, macrophages release Indian Hedgehog (Ihh), the ligand of Hedgehog (Hh) signaling pathway, to repair intestinal injury by activating intestinal stem cells, but the mechanism is still unknown. Loss of STAT1 expression can up-regulate Runx2 nuclear translocation, increase Ihh release, and promote cell proliferation, but whether this signal transduction axis play a role in intestinal injury is unknown. Our pre-experiment found that intestinal microbiota generated granisetron (GA) can inhibits the up-regulation of 5-HT receptor 3(5-HT3R), promotes Ihh expression, and improves mouse survival caused by intestinal I/R. The mechanism of GA on regulating Ihh expression and its role in intestinal I/R has not been reported. We hypothesized that when intestinal I/R happen, GA produced by the microbiota inhibits intestinal I/R-induced STAT1 activation, up-regulates Runx2 nuclear translocation, increases Ihh release, and then repairs intestinal damage. This project intends to use 5-HT3R and Ihh knockout mice and small intestine organoid ex vivo co-culture model of intestinal organoids and macrophage to study the protective role of GA and Ihh in intestinal I/R injury, which provided a theoretical basis for clinical prevention and treatment of intestinal I/R injury.
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DOI:10.1080/09537104.2021.1970124
发表时间:2021-08-29
期刊:PLATELETS
影响因子:3.3
作者:Zhou, Hui;Li, Zhifeng;Yan, Zhengzheng
通讯作者:Yan, Zhengzheng
Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischemia/reperfusion in mice
肠道微生物群衍生的琥珀酸加重小鼠肠道缺血/再灌注后的急性肺损伤
DOI:10.1183/13993003.00840-2022
发表时间:2022
期刊:European Respiratory Journal
影响因子:24.3
作者:Yi-Heng Wang;Zheng-Zheng Yan;Si-Dan Luo;Jing-Juan Hu;Mei Wu;Jin Zhao;Wei-Feng Liu;Cai Li;Ke-Xuan Liu
通讯作者:Ke-Xuan Liu
国内基金
海外基金
