GDNF-RET调控肠嗜铬细胞-潘氏细胞功能参与IBS发病的机制研究

肠易激综合征（IBS）是常见的功能性胃肠病，肠嗜铬（EC）细胞增多和5-HT水平增高是其重要的病理表现，但具体机制有待阐明。本课题组前期研究结果显示，腹泻型IBS患者肠粘膜中GDNF的含量显著高于健康对照者，且GDNF可以通过RET依赖的方式影响肠道干细胞的增殖分化。因此我们提出GDNF可以通过EC细胞和潘氏细胞影响干细胞增殖分化，促进EC细胞数量增多和5-HT分泌增强以参与IBS的发病。课题拟利用转基因动物、肠道类器官等模型，验证肠胶质细胞来源的GDNF对EC细胞增殖和5-HT分泌的影响以及后续5-HT通过潘氏细胞调节肠道干细胞的增殖分化，进而导致肠上皮中EC细胞数目增加、5-HT含量上升。而增多的EC细胞和上升的5-HT又重新参与加入循环，放大效应并导致IBS症状的发生。本研究将以GDNF为起点，从新的角度对IBS的发病机制进行探讨，并为IBS的治疗和干预提供新的靶点。

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorders, and the increase of EC cells and 5-HT level are the important pathological manifestations, however the specific mechanism has not been elucidated. Our preliminary results showed that the content of GDNF in the intestinal mucosa of diarrhea-predominant IBS patients was significantly higher than that of healthy controls, and GDNF could affect the proliferation and differentiation of intestinal stem cells in a RET dependent manner, promoting the increase of EC cells and the secretion of 5-HT. Therefore, we hypothesized that GDNF could influence the proliferation and differentiation of intestinal stem cells through EC cells and Paneth cells, promoting the EC cells hyperplasia and the 5-HT secretion, and thus participate in the pathogenesis of IBS. We intend to explore the effects of enteric glial cell derived GDNF on EC cell proliferation and 5-HT secretion using transgenic animals and in vitro cultured intestinal organoid as models. We will further explore how 5-HT regulate the proliferation and differentiation of intestinal stem cells, thus resulting in an increase in the number of EC cells and the content of 5-HT in intestinal epithelium. In addition, the increased EC cells and the higher concentration of 5-HT re-participate in the pathway, producing positive feedback and leading to the development of IBS symptoms. This study will explore the pathogenesis of IBS from a new perspective through GDNF, and provide a new target for the treatment and intervention of IBS.