Extracellular matrix in pediatric IBD

儿科 IBD 的细胞外基质

• 批准号: 6496714
• 负责人: Shukti Chakravarti
• 金额: $ 14.71万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2002-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6496714
• 关键词: Crohn's disease; adolescence (12-20); basement membrane; cellular pathology; child (0-11); clinical research; collagen; decorin; disease /disorder model; extracellular matrix; fibrosis; gene expression; genetically modified animals; heparan sulfate; human subject; inflammatory bowel diseases; intestinal mucosa; laboratory mouse; laminin; microarray technology; pathologic process; protein biosynthesis; proteoglycan; ulcerative colitis

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.

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的发病机制涉及多种因素，包括遗传、环境、微生物、免疫以及粘膜的非免疫因素。虽然IBD的免疫学一直是深入研究的焦点，但肠道细胞外基质（ECM）如何变化并促进肠道炎症的进展仍然是未知的。我们的中心假设是肠基底膜的特定改变对早期炎症至关重要，而间质ECM的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，除了某些共同特征之外，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，在其ECM改造方面可能存在根本差异。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。目标1将通过最先进的DNA微阵列技术阐明儿科和成人UC和CD患者早期和晚期的ECM基因表达谱。目的2：阐明IBD患儿和成人肠组织中选择性基底膜和间质ECM蛋白的变化。目的3将阐明在诱导和遗传性结肠炎小鼠模型中相同的ECM组分的变化。通过DNA微阵列分析UC和CD组织的基因表达谱将允许前所未有地观察区分UC和CD以及早期炎症和纤维化慢性阶段的整个转录物库。对选定ECM成分的深入研究将提供对蛋白质水平发生的改变的基本理解。一种新开发的肠纤维化动物模型将提供以下ECM变化的灵活性，从炎症的发病到建立到纤维化阶段。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，并为新的和更好的治疗方法确定可能的靶点。