KLF5在放射性肠损伤中的作用及机制研究

KLF5 (Krüppel-like factor 5) is a zinc finger-containing transcription factor, which is expressed in proliferating epithelial cells at the base of the intestinal crypts. KLF5 plays a very important role in maintaining crypt architecture and barrier function. Preliminary results showed that intestinal KLF5 protein in mice was induced upon ionizing radiation (IR). Dynamic expression of KLF5 was associated with progression of disease, suggesting that KLF5 may be crucial in repairing intestinal radiation injury. Therefore, this project will further investigate the molecular mechanisms of how KLF5 is induced by IR and the involvement of KLF5 in repairing intestinal radiation injury on molecular, cellular and animal levels. The understanding of the role and mechanism of KLF5 in radiation-induced intestinal damage will help establish the theoretical foundation for gaining insights into the pathogenesis underlying acute gastrointestinal syndrnme and developing novel therapeutic approaches.

KLF5 (Krüppel-like factor 5)是在肠隐窝底部增殖细胞中高表达的锌指蛋白转录因子，对于维持肠道隐窝结构和屏障功能起重要作用。前期研究工作表明电离辐射诱导小鼠小肠组织KLF5的表达与病情的进展具有相关性，提示KLF5可能具有参与修复放射性肠损伤的作用。鉴于此，本项目拟在分子、细胞和动物整体不同水平上，分析不同剂量照射对正常小肠上皮细胞表达KLF5的影响及其上游调控机制，明确KLF5是否参与放射性肠损伤修复并探索其参与修复的途径，从而揭示KLF5在放射性肠损伤中的作用机制，为阐明急性肠型辐射损伤机制以及寻找新的救治途径提供理论依据。

大剂量电离辐射可引起肠上皮细胞，尤其是隐窝细胞，DNA损伤，进而导致肠组织损伤，但其潜在分子机制仍不清楚。Krüppel样因子5 (Krüppel-like factor 5, KLF5)是锌指蛋白转录因子，多种组织损伤因素均可诱导KLF5表达并参与细胞增殖和存活。本项目在分子、细胞和动物整体不同水平上，分析不同剂量照射对正常小肠上皮细胞表达KLF5的影响及其上游调控机制，明确KLF5是否参与放射性肠损伤修复并探索其参与修复的途径，结果表明KLF5的表达与病情的进展具有相关性，肠道特异性敲低KLF5小鼠在受到大剂量射线照射后肠组织损伤程度加重，再生隐窝数量明显下降，难以恢复，提示KLF5在放射性肠损伤中具有重要作用。Microarray结果显示KLF5可能通过DNA损伤修复途径如碱基切除修复、错配修复、非同源末端连接修复和范可尼贫血途径来影响电离辐射引起的肠损伤，提示了KLF5的新功能。本研究深入揭示了KLF5在放射性肠损伤中的作用机制，为放射性肠损伤的救治提供了理论依据。

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