GPR35介导的色氨酸代谢感应调控KLF5修复肠粘膜损伤的分子机制

化疗肠毒性（CGT）严重限制了药物使用，阐明肠粘膜损伤修复调控机制是解决CGT临床难题的必要条件。我们已报道GPR35可通过特异性感知Trp代谢产物KA水平变化，触发化疗肠粘膜损伤修复，但其分子机制尚不明确。基因启动子区的转录因子结合位点分析发现，KLF5具有调控多种组织损伤修复基因转录的潜能。那么，GPR35是否及如何通过KLF5启动并调控肠粘膜损伤修复？进一步研究发现，KA激活PI3K/mTOR通路，并上调KLF5表达；抑制PI3K/mTOR通路，KLF5上调被阻断。由此我们提出假说：GPR35介导的Trp代谢感应通过PI3K/mTOR通路调控KLF5介导的基因转录，促进肠上皮细胞增殖迁移，修复肠粘膜损伤。本项目拟通过基因敲除、转基因鼠、临床样本分析等，阐明GPR35介导的Trp代谢感应调控KLF5在启动肠粘膜损伤修复中的关键作用及其分子机制，为CGT干预和新治疗靶点发现提供科学依据。

Chemotherapy induced gut toxicity (CGT) severely limits the use of anticancer drugs. It is necessary for solving the clinical problem of CGT to clarify the regulatory mechanism of damaged-gut mucosa repair. We have reported that G protein-coupled receptor 35 (GPR35) triggered damaged-gut mucosa induced by chemotherapy repair through sensing kynurenic acid (KA), a tryptophan (Trp) metabolite, level selectively. However, the downstream regulatory mechanism is still unknown. Based on the analysis of transcription factor binding sites in gene promoter region we found that Krüppel like factor 5 (KLF5) plays a potential role in regulating the transcription of multiple tissue repair genes. Then, does and how GPR35 initiate and regulate damaged-gut mucosa repair through KLF5? Further study we found that KA activated PI3K/mTOR pathway and upregulated KLF5 expression. Inhibiting PI3K/mTOR pathway led to the blocking of KLF5 upregulation induced by KA. Thus, we hypothesized that GPR35-mediated Trp metabolism sensing promote intestinal epithelial cells proliferation and migration through regulating KLF5 and it mediated gene transcription by PI3K/mTOR pathway, which cause the damaged-gut mucosa repair. In this project, gene knockout, transgenic rat and clinical sample analysis etc. will be utilized, to clarify the key role and molecular mechanism of GPR35-mediated Trp metabolism sensing plays in damaged-gut mucosa repair though regulating KLF5. This study would provide scientific evidence for the intervention of CGT and discovery of new therapeutic targets.