EXTRACELLULAR MATRIX IN INFLAMMATORY BOWEL DISEASE

炎症性肠病中的细胞外基质

• 批准号: 2669532
• 负责人: Alan David Levine
• 金额: $ 19.83万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2669532
• 关键词: T lymphocyte; cell adhesion; clinical research; disease /disorder etiology; extracellular matrix; human subject; immunofluorescence technique; immunopathology; inflammatory bowel diseases; integrins; intestinal mucosa; leukocyte activation /transformation; mucosal immunity; pathologic process; polymerase chain reaction; tissue /cell culture; western blottings

The multifactorial basis for the pathogenesis of inflammatory bowel disease (IBD) is being increasingly recognized, including the contribution of non immune elements to intestinal immunity and inflammation. Although various cellular components are under active investigation, the role of the acellular extracellular matrix (ECM), has been overlooked. The ECM represents a complex and dynamic mixture of macromolecular proteins with a wide range of biological activities, including a close physical and functional interaction with T-cells. This interaction is primarily mediated by integrins, a unique class of adhesion molecules that serves as a mechanical link and bidirectional transfer system for signals from the outside to the inside of a cell, and vice versa. This proposal will evaluate the role of intestinal ECM in modulation of T-cell function in the context of IBD pathogenesis. To investigate this, we have developed novel systems to study the interaction of intestinal fibroblast-derived ECM with T-cells in a mechanistic fashion. Our preliminary data clearly show that intestinal ECM is able to bind and activate T-cells. More importantly, these responses are altered when ECM derives from fibroblast of IBD-involved mucosa, and the adhesiveness for T-cells is markedly enhanced. Based on these observations, we propose to test the following central hypothesis: The enhanced capacity of IBD ECM to bind T-cells modulates mucosal immunity and contributes to chronic inflammation through integrin-mediated pathways. This central hypothesis will be tested through three specific aims: 1) Investigation of the IBD-associated changes in ECM composition responsible for increased T-cell binding; 2) Investigation of ECM-induced, integrin-mediated modulation of T-cells in normal mucosa; 3) Investigation of ECM-induced, integrin-mediated modulation of T-cells in IBD-involved mucosa. The cellular, biochemical and molecular elements and experimental systems necessary to perform the proposed studies are available, have been tested and proved to be workable. We believe this proposal will generate original information needed for a novel and more global approach to the pathogenesis of IBD.

炎症性肠病发病机制的多因素基础 疾病（IBD）越来越受到人们的重视，包括 非免疫元素对肠道免疫的贡献 炎。 尽管各种细胞成分都处于活跃状态 研究表明，无细胞细胞外基质 (ECM) 的作用 被忽视了。 ECM 代表了复杂且动态的混合体 具有广泛生物活性的大分子蛋白质， 包括与 T 细胞密切的物理和功能相互作用。 这种相互作用主要由整合素介导，整合素是一类独特的 粘附分子作为机械连接和双向 从细胞外部到内部的信号传输系统， 反之亦然。 该提案将评估肠道 ECM 的作用 IBD 发病机制中 T 细胞功能的调节。 为了研究这个问题，我们开发了新的系统来研究 肠成纤维细胞来源的 ECM 与 T 细胞的相互作用 机械时尚。 我们的初步数据清楚地表明肠道 ECM 能够结合并激活 T 细胞。 更重要的是，这些 当 ECM 源自 IBD 相关成纤维细胞时，反应会发生改变 粘膜，T细胞的粘附力显着增强。 基于 根据这些观察结果，我们建议测试以下核心 假设：IBD ECM 结合 T 细胞调节能力增强 粘膜免疫并通过以下方式促进慢性炎症 整合素介导的途径。 这个中心假设将被检验 通过三个具体目标： 1) 调查 IBD 相关疾病 ECM 成分的变化导致 T 细胞结合增加； 2） ECM 诱导、整合素介导的 T 细胞调节的研究 在正常粘膜中； 3) ECM诱导、整合素介导的研究 IBD 相关粘膜中 T 细胞的调节。 细胞、生化 以及执行该操作所需的分子元件和实验系统 拟议的研究是可用的，已经过测试并被证明是 可行的。 我们相信该提案将产生原始信息 需要一种新的、更全面的方法来研究 IBD 的发病机制。