谷氨酰胺代谢感受器在肠粘膜损伤修复中的价值研究

The research in metabolic regulation is frontier of life science. The etiology and mechanism of protracted course in inflammatory bowel disease (IBD) are far from illuminated. Repair of intestinal epithelial cells is the foundation of IBD recovery, which demands massive nutrients. Glutamine (Gln) is a significant amino acid in the recovery of intestinal tracts, but its sensor and regulation mechanism is remained to be elucidated. We discovered for the first time that glutamine synthase inhibitor could induce the occurrence of IBD independently. This model of induced-colonitis based on our study has been applied for a national patent (No. 201610116025.7). We further found that endogenic synthesis of glutamine is the crucial process of restoration in impaired intestine and mTORC2 might be a glutamine sensor. Thus, we hypothesize that insufficient synthesis of glutamine may be the key factor of impaired intestine and protracted course in IBD. If granted, we plan to elucidate the role of glutamine and its sensor in the repair of intestinal epithelia in the level of cell, animal model and IBD patients respectively. Briefly, we will focus on the regulation of endogenous glutamine on colon stem cell and immunity, the effect of gut microbiota and their metabolites on the sensor of glutamine, and the screen of small molecule agonists of mTORC2. This project will establish the value of glutamine in IBD treatment and provide novel intervention thought from the point of improving endogenic synthesis of glutamine, which shows great clinical value.

代谢调控研究是生命科学前沿。炎症性肠病（IBD）的病因及迁延不愈机制远未阐明。上皮细胞修复是IBD愈合的基础，且代谢需求巨大。谷氨酰胺（Gln）是肠道修复中的重要氨基酸，但其感受器及调控机制目前尚不明确。我们首次发现：Gln合成酶抑制剂可独立诱导IBD发生，基于此建立的结肠炎模型已申报国家专利（NO.201610116025.7）；进一步发现Gln的内源性合成是肠道损伤修复的重要过程，mTORC2或为其感受器。据此提出：Gln合成不足或是IBD肠道损伤及迁延不愈的重要因素。拟在细胞、动物模型及IBD病人中，从内源性Gln合成对肠道干细胞及肠道免疫的调控、肠道菌群及其代谢物对Gln感受器的影响、mTORC2小分子激动剂筛选等方面，全面阐明Gln及其感受器在肠道上皮修复中的作用。本项目将确立Gln对IBD的治疗价值，并从改善Gln内源性合成角度提供IBD干预新思路，具有重要临床价值。

谷氨酰胺是肠道修复中的关键氨基酸，对炎症性肠病（IBD）具有重要治疗作用，但其相关的内源性调节机制尚不明确。课题组前期发现，药物性抑制内源性谷氨酰胺合成可引起肠道菌群紊乱，诱导小鼠肠道损伤，提示谷氨酰胺合成酶（Glul）可能有肠道保护功能，并可作为谷氨酰胺缺乏的重要感受器。本项目从代谢调控角度剖析IBD的发病机制，探索谷氨酰胺内源性合成不足对肠道免疫稳态和肠道干细胞的影响，阐明了谷氨酰胺内源性合成不足是肠道损伤的重要因素，而Glul是重要感知分子。揭示了炎症状态对Glul的抑制可以显著活化巨噬细胞且促进其趋化因子的分泌，或者影响肠道干细胞数量及功能，进而加重肠道损伤，这些可能都是导致IBD迁延不愈的重要原因。目前IBD的治疗方法副作用明显，且久治不愈，本项目提出Glul腺相关病毒、CCL2/7中和抗体及α-KG增补剂或可作为IBD新的治疗策略。总之，本项目首次从代谢调控角度解释IBD发病机制，探索治疗策略，具有重要的基础和临床转化价值。