Extracellular matrix in pediatric IBD

儿科 IBD 的细胞外基质

• 批准号: 6652808
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2003-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652808
• 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，引发和永久性事件与免疫调节异常，组织损伤和最终临床症状有关。从遗传，环境，微生物，免疫学以及粘膜的非免疫元素中引用了多种因素，涉及IBD发病机理。尽管IBD的免疫学一直是激烈研究的重点，但肠外基质基质（ECM）如何变化并有助于肠道炎症的发展。我们的中心假设是，肠底膜膜的特定变化至关重要，在早期炎症中有效，而间质ECM的合成和调节的改变对于从早期到慢性疾病阶段的疾病进展至关重要。此外，临床证据表明，除了某些共同特征，克罗恩氏病（CD）和溃疡性结肠炎（UC），这是两个IBD亚型，是不同的实体，其ECM改头换面可能存在根本差异。当前的提案将通过阐明CD和UC患者的IBD早期和慢性阶段的ECM变化来调查这一问题。 AIM 1将通过最先进的DNA微阵列技术在小儿和成人患者的早期和晚期阶段阐明UC和CD晚期的ECM基因表达谱。 AIM 2将阐明小儿和成人IBD患者的肠组织中选定的基底膜和间质ECM蛋白的变化。 AIM 3将阐明在诱发的结肠炎和遗传鼠模型中同一集ECM成分中的变化。 DNA微阵列对UC和CD组织的基因表达分析将允许对将UC与CD与CD区分开的整个转录本的曲目以及炎症和纤维化的慢性阶段进行前所未有的观察。对选定的ECM组件的深入研究将提供对蛋白质水平发生的变化的基本理解。新开发的肠纤维化动物模型将具有遵循从发作到确定到炎症纤维化阶段的ECM变化的灵活性。最终，基因表达研究将为与人类IBD的动物模型进行全面比较，并确定新的和更好治疗方法的可能目标。