PEDIATRIC IBD--KEY TO EARLY PATHOGENIC EVENTS

该计划项目的总体目标是通过研究克罗恩病和溃疡性结肠炎的儿童，以及胃肠道炎症动物模型中疾病的早期到晚期的进展，填补目前对IBD发病机制认识的一个主要空白。该建议是IBD病理生理学、肠道免疫、粘膜细胞因子、结肠炎和胃炎的动物模型以及肠道炎症中免疫-非免疫细胞相互作用等多学科专业知识的自然产物。该计划项目将通过测试四个研究项目中提出的特定假设来调查肠道炎症早期和晚期事件的机制联系。项目1：儿童早期IBD是由于对共生菌群的抗原失去耐受性所致，其持久性导致IBD的慢性化。项目2：IBD小鼠模型的炎症是由粘膜T细胞对肠道细菌抗原的反应引发的，在疾病的晚期通过粘膜免疫和非免疫细胞维持的促炎反应而持久存在。项目3：慢性胃肠道炎症是由对来自正常肠道菌群的抗原刺激产生的异常免疫反应引起的，这种反应受到免疫和幽门螺杆菌生物的存在或不存在的调节。项目4：粘膜基底膜细胞外基质成分的特定变化在早期炎症中起关键作用，而间质细胞外基质的合成和调节变化促进炎症从疾病的早期发展到晚期。这些项目将使用最先进的方法学策略进行，包括评估儿童和成人IBD患者对正常肠道抗原的耐受性，对早期和晚期肠道炎症模型的基因缺陷小鼠的免疫调节研究，这些模型中共生细菌和感染细菌的定植，用于肠道炎症差异基因表达的DNA微阵列系统，人类和小鼠IBD模型的细胞外基质基因和蛋白表达，以及诱导正常和蛋白多糖缺陷小鼠的肠道纤维化。这四个项目将由三个服务核心提供支助：患者核心(A)、动物核心(B)和行政核心(C)。

The overall goal of the Program Project is to fill a major gap in current knowledge of IBD pathogenesis by studying children with Crohn's disease and ulcerative colitis, and the progression of early to late stages of disease in animal models of gastrointestinal inflammation. The proposal is the natural outcome of a vigorous and multi-disciplinary expertise in IBD pathophysiology, intestinal immunity, mucosal cytokines, animal model of colitis and gastritis, and immune-non immune cell interaction in intestinal inflammation. The Program Project will investigate will investigate mechanistic links of early to late events of gut inflammation by testing the specific hypotheses proposed in four Research Projects. Project 1: Early IBD in children results from loss of tolerance to antigens of the commensal flora, and its persistence contributes to the chronicity of IBD. Project 2: Inflammation in murine models of IBD is initiated by mucosal T-cell responses to enterobacterial antigens, and it is perpetuated during the late stage of disease by a pro-inflammatory response maintained by mucosal immune and non immune cells. Project 3: Chronic gastrointestinal inflammation results from an aberrant immune response against antigenic stimuli derived from the normal enteric flora, and this response is modulated by immunization and the presence or absence of Helicobacter organisms. Project 4: Specific changes in the composition of the extracellular matrix of mucosal basement membrane contributes crucially to early inflammation, while altered synthesis and modulation of interstitial extracellular matrix foster progression of inflammation from the early to the late stages of disease. These proje3cts will be performed using state-of-the-art methodological strategies including evaluation of tolerance to normal enteric antigens in pediatric and adult IBD patients, immunoregulatory studies in gene-deficient mice with early and late models of intestinal inflammation, colonization by commensal and infectious bacteria in these models, DNA microarray systems for differential gene expression in intestinal inflammation, extracellular matrix gene and protein expression in human and murine models of IBD, and induction of intestinal fibrosis in normal and proteoglycan-deficient mice. The four Projects will be supported by three Service Cores: a Patient Core (A), an Animal Core (B) and an Administrative Core (C).