Extracellular matrix in pediatric IBD

炎症性肠病（IBD）是一种进行性多步骤疾病，其起始和持续事件与免疫调节异常、组织损伤和最终的临床症状相关。IBD的发病涉及多种因素，包括遗传、环境、微生物、免疫以及粘膜的非免疫因素。虽然IBD的免疫学一直是激烈研究的焦点，但肠道细胞外基质（ECM）如何改变并促进肠道炎症的进展仍在很大程度上未知。我们的中心假设是，肠基底膜的特异性改变对早期炎症起着至关重要的作用，而间质ECM合成和调节的改变在疾病从早期到慢性阶段的进展中很重要。此外，临床证据表明，除了某些共同特征外，克罗恩病（CD）和溃疡性结肠炎（UC）这两种IBD亚型是不同的实体，它们的ECM改造可能存在根本差异。目前的提案将通过阐明儿童和成人CD和UC患者IBD早期和慢性阶段的ECM变化来研究这一点。目的1将通过最先进的DNA微阵列技术阐明儿科和成人UC和CD早期和晚期的ECM基因表达谱。目的2将阐明儿童和成人IBD患者肠组织中选定的基底膜和间质ECM蛋白的变化。目的3将阐明同一组ECM成分在诱导和遗传小鼠结肠炎模型中的变化。通过DNA微阵列对UC和CD组织进行基因表达谱分析，可以前所未有地观察UC和CD以及早期和慢性炎症和纤维化的全部转录本。对所选ECM成分的深入研究将提供对发生在蛋白质水平上的改变的基本理解。一种新开发的肠纤维化动物模型将提供从炎症开始到建立到纤维化阶段的ECM变化的灵活性。最终，基因表达研究将为动物模型与人类IBD的全面比较提供技术，并为新的更好的治疗方法确定可能的靶点。

Inflammatory bowel disease (IBD) is a progressive multi-step disease, with initiating and perpetuating events associated with immunoregulatory abnormalities, tissue damage and eventually clinical symptoms. Multiple factors, from genetic, environmental, microbial, immunologic, as well as non-immune elements of the mucosa are cited as involved in IBD pathogenesis. While the immunology of IBD has been the focus of intense studies, how the intestinal extracellular matrix (ECM) changes and contributes to progression of intestinal inflammation remains largely unknown. Our central hypothesis is that specific alterations in the intestinal basement membrane contribute crucially to early inflammation, while altered synthesis and modulation of interstitial ECM are important in progression of disease from early to chronic stages of disease. Furthermore, clinical evidence suggests that beyond certain common features, Crohn's disease (CD) and ulcerative colitis (UC), the two IBD subtypes, are diverse entities, with possibly fundamental differences in their ECM makeover. The current proposal will investigate this by elucidating ECM changes underlying early and chronic stages of IBD in pediatric and adult patients with CD and UC. Aim 1 will elucidate ECM gene expression profiles in early and late stages of UC and CD in pediatric and adult patients by state-of-the-art DNA microarray techniques. Aim 2 will elucidate changes of selected basement membrane and interstitial ECM proteins in bowel tissues from pediatric and adult IBD patients. Aim 3 will elucidate changes in the same set of ECM components in induced and genetic murine models of colitis. Gene expression profiling of UC and CD tissue by DNA microarray will allow an unprecedented viewing of the entire repertoire of transcripts that differentiate UC from CD, as well as early from chronic stages of inflammation and fibrosis. In-depth studies of selected ECM components will provide a basic understanding of alterations that occur at the protein level. A newly developed animal model of intestinal fibrosis will offer the flexibility of following ECM changes from the onset to established to fibrosis stages of inflammation. Ultimately, the gene expression studies will provide the technology for a comprehensive comparison of animal models with human IBD and identify possible targets for new and better therapeutic approaches.