5-HT4受体激动剂促Nestin+肠神经干细胞分化在糖尿病肠神经再生中的机制研究

Enteric nervous system (ENS) maintains gastrointestinal motility. ENS is the most vulnerable target in diabetic metabolism (DM) condition. It has been reported that Nestin-expressing enteric progenitor cells could give up to neurogenesis in adult ENS, while whether neurogenesis exists in diabetic colonic dysmotility and the possible mechanism are unclear. We have found that there were more Nestin-expressing enteric progenitor cells and more proliferation of them in diabetic rats’ colon with 5-HT4 receptor agonist therapy. We hypothesis that: both ENS injury and ENS neurogenesis exist in gastrointestinal tract, and the mechanism could be proliferation and differentiation of Nestin-expressing cells via activation of 5-HT4 receptor/cAMP/PKA signaling. Collected diabetic colon sample, diabetes animal model and Nestin-expressing enteric progenitor cells will be used to confirm the neurogenesis by Nestin-expressing enteric progenitor cells and illustrate the mechanism of 5-HT4 receptor/cAMP/PKA signal in neurogenesis by Nestin-expressing progenitor cells. Intraperitoneal injection BrdU, 5-HT4 receptor agonist or inhibitor interference are experiments methods. Therefore, our study provides a potential target for clinical intervention in diabetic gastrointestinal motility disorders.

肠神经系统（ENS）维持正常胃肠动力。文献报道，成体ENS损伤时，源于肠神经干细胞（Nestin+）的再生可修复ENS；并且激活5-HT4受体也可促进ENS再生。糖尿病（DM）时ENS最易受损，表现为肠动力功能紊乱，但DM时是否存在ENS再生尚不明确。同时，我们前期工作发现：5-HT4受体激动剂作用DM大鼠可促Nestin+干细胞数量明显增加。故提出本课题：DM病程中存在ENS损伤、可能伴有ENS再生，使用5-HT4受体激动剂可能激活5-HT4受体及其下游cAMP/PKA信号通路来介导Nestin+干细胞的分化与增殖，促进ENS修复、再生，改善结肠动力。拟采用：DM动物模型及组织、细胞培养，使用BrdU腹腔在体注射追踪干细胞分化去向、5-HT4受体激动剂/抑制剂干预5-HT4受体活性等方法验证上述假说，探讨促DM时ENS再生的可能作用及机制，为DM胃肠动力障碍的防治提出新的调控靶点。