空结肠吻合型SBS大鼠的残余空肠单细胞表达图谱的构建及GLP-2促进残余空肠粘膜增生的作用机制研究

短肠综合征（SBS）是慢性肠衰竭的主要原因，但SBS目前的病理生理机制研究不清，同时治疗困难重重。我们前期研究成功构建了空结肠吻合型SBS大鼠残余空肠的单细胞表达图谱，初步阐述了SBS肠适应过程中重要的病理生理变化，如静止型Krt19+干细胞被激活、Reg再生基因家族表达上调等，进一步研究可为SBS的治疗提供新靶点。另外，GLP-2是治疗SBS的新希望，但目前其作用机制仍存在较大争议。我们通过构建单细胞表达图谱，明确了GLP-2受体高表达于肠道成纤维细胞，GLP-2可能通过上调成纤维细胞外泌体中的Wnt3a及EGF的含量而促进SBS的肠粘膜增殖及肠适应。在此基础上，拟申报本课题，继续完善和深化本研究，为SBS的治疗挖掘新靶点，为GLP-2的临床运用提供理论支持，为SBS的外泌体治疗提供新思路，为SBS的治疗窘境带来新希望。

Short bowel syndrome (SBS) is the main cause of chronic intestinal failure. However, at present, the pathophysiological mechanism of SBS is unclear and the treatment of SBS is quite difficult. In our previous study, we successfully constructed the single-cell atlas of the residual jejunum in SBS rats with jejunocolonic anastomosis, and preliminarily demonstrated the important pathophysiological changes in process of intestinal adaptation under SBS, such as the activation of static krt19 + stem cells and the up-regulation of Reg regeneration gene family, which can provide new targets for the treatment of SBS. GLP-2 has become the new hope for treatment of SBS, but its mechanism is still controversial. By constructing the single cell expression profile of SBS, we confirmed that GLP-2 receptor is highly expressed in intestinal fibroblasts. GLP-2 may promote the intestinal mucosal proliferation and intestinal adaptation of SBS by up regulating the contents of Wnt3a and EGF in fibroblast-derived exosomes. Based on the previous research, the applicant applies for this project to improve and deepen this study so as to explore new targets for the treatment of SBS and provide theoretical support for the clinical application of GLP-2. The completion of this project will provide new ideas for exosomes in the treatment of SBS, and bring new hope for the treatment dilemma of SBS.