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，其引发和持续的事件与免疫调节异常、组织损伤和最终的临床症状相关。 IBD 发病机制涉及遗传、环境、微生物、免疫以及粘膜非免疫因素等多种因素。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) 如何变化以及如何促进肠道炎症的进展仍然很大程度上未知。我们的中心假设是，肠道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对于疾病从早期阶段到慢性阶段的进展很重要。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，其 ECM 改造可能存在根本差异。目前的提案将通过阐明患有 CD 和 UC 的儿科和成人 IBD 早期和慢性阶段的 ECM 变化来对此进行研究。目标 1 将通过最先进的 DNA 微阵列技术阐明儿科和成人患者 UC 和 CD 早期和晚期的 ECM 基因表达谱。目标 2 将阐明儿科和成人 IBD 患者肠组织中选定基底膜和间质 ECM 蛋白的变化。目标 3 将阐明诱导和遗传小鼠结肠炎模型中同一组 ECM 成分的变化。通过 DNA 微阵列对 UC 和 CD 组织进行基因表达谱分析，将能够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本。对选定的 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了解。新开发的肠纤维化动物模型将提供跟踪 ECM 从炎症发作到建立到纤维化阶段的变化的灵活性。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，并确定新的、更好的治疗方法的可能靶点。