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)是一种进行性的多步骤疾病，其始发和持续性事件与免疫调节异常、组织损伤和最终临床症状有关。多种因素，包括遗传、环境、微生物、免疫学以及粘膜的非免疫因素，都被认为与IBD的发病有关。虽然IBD的免疫学一直是密集研究的焦点，但肠道细胞外基质(ECM)如何变化并促进肠道炎症的进展在很大程度上仍不清楚。我们的中心假设是，肠道基底膜的特异性改变在早期炎症中起关键作用，而间质ECM的合成和调节改变在疾病从早期到慢性阶段的进展中起重要作用。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。目前的建议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利用先进的DNA微阵列技术研究儿童和成人UC和CD早期和晚期的细胞外基质基因表达谱。目的2阐明小儿和成人IBD患者肠道组织中选择的基底膜和间质ECM蛋白的变化。目的3将阐明诱导性和遗传性结肠炎小鼠模型中同一组细胞外基质成分的变化。利用DNA微阵列对UC和CD组织进行基因表达谱分析，将允许前所未有地查看区分UC和CD的整个转录库，以及区分慢性炎症和纤维化的早期转录库。对选定的ECM成分的深入研究将使我们对蛋白质水平上发生的变化有一个基本的了解。一种新开发的肠纤维化动物模型将提供从炎症的发病到确诊再到纤维化阶段ECM变化的灵活性。最终，基因表达研究将为全面比较动物模型和人类IBD提供技术，并为新的更好的治疗方法确定可能的靶点。