肠道神经胶质细胞在代谢性炎症中的作用和机制研究

肥胖不仅仅是代谢性疾病，也是系统性慢性代谢炎症，免疫系统参与调控其病理进程。肠道局部免疫是肥胖等代谢炎症的重要调控环节。肠道本身的神经系统对肠道的粘膜屏障功能有重要的调控作用，然而它们在代谢性疾病中的作用常期以来并不清楚。我们课题组在小鼠高脂饮食诱导的肥胖模型中发现，早期在未见明显的脂肪和肠道炎症的情况下，肠道就已开始高表达神经营养因子artemin 基因，我们推测肠道自身的神经系统，特别是肠道胶质细胞作为肠道粘膜上皮细胞和免疫细胞之间的桥梁，在代谢炎症中可能起到重要作用。本研究将通过细胞特异性基因敲除小鼠模型，结合体外细胞培养和分子生物学手段系统研究肠道神经胶质细胞在肠道免疫活化以及肥胖及其相关的胰岛素抵抗中的作用及可能的细胞和分子机制。本项研究的完成可从一个新的角度阐述肥胖及代谢疾病的发病机理，并为临床通过干预肠道局部炎症来治疗系统性代谢疾病的新模式提供有力的理论依据和可能的靶标。

Obesity and its associated metabolic diseases, including insulin resistance (IR) and type 2 diabetes (T2D), have become global diseases that carry considerable morbidity and mortality. The cellular and molecular pathways that lead to the pathogenesis of obesity remain incompletely understood. Current dogma is that metabolic diseases are not simply metabolic disorders but rather a systemic inflammatory diseases caused by a special type of chronic inflammation called meta-inflammation. Recent evidence has pointed to the gut as a key site in regulating obesity. The gut has large number of nerve cells that can potentially regulate mucosal integrity, however whether the enteric nervous system can regulate meta-inflammation during obesity is not known. In the diet-induced obese mouse model, we found an increase expression of glial cell-derived neurotrophic factor family ligand artemin gene in the gut during early phase of high-fat diet feeding. We hypothesize that the enteric nervous system, especially the enteric glial cells, might play important roles in regulating meta-inflammation by orchestrating the cross-talk among the mucosal epithelium, the enteric nerve system and the gut immune systems. We will use cell type-specific gene knockout mouse model in combination with in vitro cellular and molecular technologies to test our hypothesis. This proposal will further improve our understanding of the pathogenesis of obesity and its related metabolic diseases and could potentially lead to novel obesity-related therapies by controlling gut local inflammation.