PEDIATRIC IBD--KEY TO EARLY PATHOGENIC EVENTS

该项目的总体目标是通过研究克罗恩病和溃疡性结肠炎儿童，以及胃肠道炎症动物模型的早期到晚期疾病进展，填补目前对IBD发病机制的主要空白。该提案是IBD病理生理学，肠道免疫，粘膜细胞因子，结肠炎和胃炎动物模型以及肠道炎症中免疫-非免疫细胞相互作用的多学科专业知识的自然结果。该项目将通过测试四个研究项目中提出的具体假设来研究肠道炎症早期和晚期事件的机制联系。项目1：儿童早期IBD是由于对共生菌群抗原的耐受性丧失，其持续性导致IBD的慢性。项目2：小鼠IBD模型中的炎症是由粘膜t细胞对肠杆菌抗原的反应引发的，在疾病晚期，它通过粘膜免疫细胞和非免疫细胞维持的促炎反应而持续存在。项目3：慢性胃肠道炎症是由于对来自正常肠道菌群的抗原刺激的异常免疫反应引起的，这种反应是由免疫和幽门螺杆菌的存在或不存在调节的。项目4：粘膜基底膜细胞外基质组成的特异性变化对早期炎症起着至关重要的作用，而间质细胞外基质合成和调节的改变促进了炎症从疾病早期到晚期的进展。这些项目将采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，对具有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性细菌的定植，用于肠道炎症差异基因表达的DNA微阵列系统。细胞外基质基因和蛋白在人和小鼠IBD模型中的表达，以及在正常和蛋白聚糖缺乏小鼠中诱导肠道纤维化。这四个项目将由三个服务核心提供支持：病人核心(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).