Enteric Neuronal Development as a Determinant of Intestinal Inflammation

描述（由申请人提供）：这份申请是为了支持我在哥伦比亚大学的职业发展，由Michael D. Gershon（肠道神经生理学/发育），Charalabos Pothoulakis（肠道炎症）和Lloyd Mayer（免疫学）赞助。培训计划包括课程、指导研究和受保护的研究时间。我的研究旨在分析肠神经系统（ENS）对肠道炎症和肠壁神经免疫相互作用的病理生理的推定贡献。据报道，炎症性肠病（IBD）或肠神经节瘤病患者肠道炎症区域的肠神经元数量增加。在人类中，不可能确定神经元增生是否早于肠道炎症，是肠道炎症的结果，还是导致了肠道炎症的严重程度。我们用了as

DESCRIPTION (provided by applicant): This application is to support my career development at Columbia University under the sponsorship of Michael D. Gershon (enteric neurophysiology/development), Charalabos Pothoulakis (intestinal inflammation) and Lloyd Mayer (immunology). The training plan includes courses, mentored research, and protected research time. My investigation is designed to analyze putative contributions of the enteric nervous system (ENS) to the pathophysiology of intestinal inflammation and neuroimmune interactions in the bowel wall. Increased numbers of enteric neurons have been reported in inflamed regions of the gut in patients with inflammatory bowel disease (IBD) or intestinal neurogangliomatosis. It is impossible to determine in humans whether neuronal hyperplasia predates intestinal inflammation, results from it, or contributes to its severity. We have used, as genetic models, mice in which the ENS is hyperplastic (NSE-noggin mice) or hypoplastic (Hand2+/- mice) to test the hypothesis that ENS hyperplasia is proinflammatory. Preliminary data show that measures of severity (survival, clinical and histological scores, intestinal expression of genes encoding proinflammatory molecules, levels of neutrophil elastase and p50 NFκB) of TNBS- and DSS-induced colitis are higher in NSE- noggin and lower in Hand2+/- mice than in their wild-type (WT) littermates. In neither mouse, however, are differences from WT found in measures of the severity (edema, T cell and neutrophil infiltration, and expression of IL1ß , IFNγ, and TNFα) of delayed type hypersensitivity evoked in the ears with dinitrofluorobenzene. Transgene effects on inflammation are thus limited to the bowel. These observations are consistent with the hypotheses that ENS hyperplasia contributes to the severity of intestinal inflammation and, potentially also therefore, to the pathogenesis of IBD. I now propose to investigate mechanisms by which the ENS affects intestinal inflammation. I will determine whether the proinflammatory effects of ENS hyperplasia are due to altered (i) intestinal barrier function, (ii) innate immunity, and (iii) immunoregulation. The ability of enterc neurons to affect TLR4 and TLR5 signaling at baseline and during inflammation will be examined. I will determine the effect of the ENS on the integrity of epithelial tight junctions and basal laminae as well as bidirectional translocation of macromolecules across the intestinal epithelium. Analyses of numbers, location, and proportions of regulatory T cell (Treg) subsets (from lamina propria and spleen) as well as their ability to inhibit lymphocyte proliferation will e employed to test hypotheses that ENS hyperplasia decreases Treg number and/or function. Intestinal inflammation occurs in intestinal disorders besides IBD, including necrotizing enterocolitis, infectious diarrhea, and irritable bowel syndrome; the ENS may contribute to any or all of them. Knowledge of interactions between the ENS and inflammatory effectors, therefore, has the potential to transform understanding and, ultimately, treatment of many intestinal disorders.