The Extracellular Matrix Inflammatory Bowel Disease

细胞外基质炎症性肠病

• 批准号: 6617832
• 负责人: Alan David Levine
• 金额: $ 32.8万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617832
• 关键词: T cell receptor; T lymphocyte; apoptosis; atomic force microscopy; biological signal transduction; cell adhesion; cell component structure /function; cell growth regulation; cell proliferation; clinical research; confocal scanning microscopy; cytokine; disease /disorder etiology; extracellular matrix; human subject; immunopathology; inflammatory bowel diseases; integrins; intermolecular interaction; intestinal mucosa; leukocyte activation /transformation; mucosal immunity; pathologic process; patient oriented research; phosphorylation; tissue /cell culture

DESCRIPTION (provided by applicant): Numerous etiologies have been investigated for the pathogenesis of inflammatory bowel disease (IBD), with significant focus on a dysfunctional mucosal immune response. However, non-immune parameters, especially components of the cellular interstitial network of proteins, glycoproteins, and proteoglycans known as the extracellular matrix (ECM) have been overlooked. Our findings, generated during the first three years of the current funding cycle, demonstrated (a) that regulation of intestinal lamina propria T cells (LPT) is altered by the combined response to activation through the T cell receptor/CD3 complex and ECM engagement of integrins, (b) that the ECM microenvironment is capable of instructing newly arrived T cells with a mucosal adhesive phenotype, (c) that this resultant adhesive phenotype educates (LPT) to interact with the three-dimensional ECM via distinct integrin molecules, shaping the ensuing immune response by modulating T cell activation and differentiation, and (d) that these changes in T cell function and phosphorylation are paralleled by Beta1 integrin mediated cellular polarization and the asymmetrical distribution of TCR signaling complexes. To explore these novel and exciting findings, we have assembled a multidisciplinary team of investigators with expertise in IBD, molecular imaging, cell cycle regulation, apoptosis, and mucosal immunology, and developed new techniques to study ECM from normal and IRD mucosa. These techniques will be complemented by biochemical, immunological, and molecular approaches to test the following central hypothesis: ECM engagement of select integrins on mucosal T cells modulates their signaling and function and contributes to chronic inflammation. This hypothesis will be tested by four specific aims: (1) Characterize integrin-mediated regulation of T cell function, (2) Investigate the role of Beta1 integrins in regulating T cell compartmentalization before and after T cell activation, and the resulting changes in proximal TCR signaling (3) Explore the IBD-associated changes in ECM structure responsible for increased T cell binding, and (4) Investigate ECM-induced modulation of T cells in IBD mucosa. We believe therapeutic approaches to IBD that target cell adhesion molecules can be substantially improved once the key mechanisms by which integrins mediate inflammation are clearly defined.

描述（由申请人提供）：已经研究了炎症性肠病（IBD）发病机制的多种病因，重点关注粘膜免疫应答功能障碍。然而，非免疫参数，特别是蛋白质、糖蛋白和蛋白聚糖的细胞间质网络的组分（称为细胞外基质（ECM））一直被忽视。我们的研究结果是在当前资助周期的前三年期间产生的，表明（a）肠固有层T细胞（LPT）的调节被通过T细胞受体/CD 3复合物和整合素的ECM接合的活化的组合应答改变，（B）ECM微环境能够指导新到达的具有粘膜粘附表型的T细胞，（c）这种所得的粘附表型诱导（LPT）通过不同的整联蛋白分子与三维ECM相互作用，通过调节T细胞活化和分化形成随后的免疫应答，以及（d）这些T细胞功能和磷酸化的变化是由β 1整合素介导的细胞极化和细胞内不对称分布引起的。TCR信号复合物。为了探索这些新颖而令人兴奋的发现，我们组建了一个多学科的研究团队，他们在IBD，分子成像，细胞周期调控，细胞凋亡和粘膜免疫学方面具有专业知识，并开发了新技术来研究正常和IRD粘膜的ECM。这些技术将通过生物化学，免疫学和分子方法进行补充，以测试以下中心假设：选择整合素对粘膜T细胞的ECM参与调节其信号传导和功能，并有助于慢性炎症。这一假设将通过四个具体目标进行检验：（1）表征整联蛋白介导的T细胞功能调节，（2）研究β 1整联蛋白在调节T细胞活化前后T细胞区室化中的作用，以及近端TCR信号传导的结果变化，（3）研究负责增加T细胞结合的ECM结构中IBD相关的变化，（4）研究ECM对IBD粘膜T细胞的调节作用。我们相信，一旦明确了整合素介导炎症的关键机制，靶向细胞粘附分子的IBD治疗方法就可以得到实质性改善。