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Extracellular Matrix in Inflammatory Bowel Disease

炎症性肠病中的细胞外基质

基本信息

批准号：
7925821
负责人：
Alan David Levine
金额：
$ 34.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7925821
关键词：
Actins Adhesions Adhesives Adverse effects Affect Amino Acids Anatomy Area Atomic Force Microscopy Attention Basement membrane Binding Biochemical Blood Cell Adhesion Cell Adhesion Molecules Cell Cycle Progression Cell Lineage Cell physiology Cells Cellular Morphology Clinical Clinical Medicine Collagen Colon Communication Complex Confocal Microscopy Constipation Crohn&apos s disease Cytoskeletal Modeling Cytoskeleton DNA Sequence Rearrangement Data Deposition Diarrhea Disease ECM receptor Electron Microscopy Epithelium Evaluation Event Extracellular Matrix Extracellular Matrix Proteins Family Family member Feeds Fibrillar Collagen Fibroblasts Fibronectins Fibrosis Filament Focal Adhesions Generations Glycoproteins Guanosine Triphosphate Phosphohydrolases Head Host Defense Human Immune System Diseases Immune response Immunity Infection Inflammation Inflammatory Inflammatory Bowel Diseases Injury Integrins Intermediate Filaments Intestines Knowledge Lamina Propria Leukocytes Ligation Location Lower Abdominal Pain Mechanics Mediating Microfilaments Microtubules Molecular Molecular Conformation Monomeric GTP-Binding Proteins Morphology Mucous Membrane Muscle Cramp Muscle Rigidity Muscularis Mucosa N-terminal Pathogenesis Pathway interactions Patients Pattern Phenotype Phosphorylation Phosphotransferases Process Property Protein-Serine-Threonine Kinases Proteins Proteoglycan Publishing Receptor Signaling Recurrence Regulation Reporting Research Research Personnel Rest Roentgen Rays Role Scanning Serine Serous Membrane Severities Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Signaling Protein Small Intestines Structure Submucosa Surface System T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Tyrosine Phosphorylation Ulcer Ulcerative Colitis Vimentin absorption biological systems cell motility chemokine design imprint interstitial member migration peripheral blood polymerization receptor-mediated signaling repaired response rho rho GTP-Binding Proteins tissue culture

项目摘要

Tissue damage in Ulcerative colitis (UC) is predominantly ulceration of the epithelium and its underlying basement membrane. In contrast, Crohn’s disease (CD) is characterized by excessive deposition of fibrillar collagen in the lamina propria, muscularis mucosa, submucosa, muscularis propria, and serosa. Thus, in both forms of inflammatory bowel disease (IBD) tissue remodeling and the destruction and restitution of the interstitium are continual and dynamic processes that contribute to anatomical destruction and major clinical consequences. In that mucosal T lymphocytes are enmeshed in the complex and highly organized network of proteins, glycoproteins, and proteoglycans known as the extracellular matrix (ECM), we propose that the chronicity, exacerbation, and recurrence of IBD are multifactorial, involving a process by which the intermingled pathogenic T cells adversely affects tissue injury and fibrosis, and vice versa. Our published and preliminary results show that integrin-mediated adhesion to the ECM is a central event in the generation of an immune response. Therefore, we postulate that ECM adhesion and accessory function is also a pivotal mechanism that modulates IBD. We report that the signal transduction pathway initiated by collagen in an effector/memory T cell is different from that initiated by fibronectin. In addition, the Rho family member of small GTPases, which regulate cytoskeletal reorganization, activated in a T cell adherent to fibronectin differs from that activated when the T cell is bound to collagen, and that the pattern of serine phosphorylation on the head domain of vimentin (the key component of the intermediate filament in T cells) is similarly distinct. We also demonstrate that a three dimensional, native ECM synthesized by human intestinal fibroblasts (HIF) from a control patient initiates a signal transduction cascade in T cells different from that initiated by a native matrix secreted by HIF from patients with Crohn’s disease. When we couple the observation that (i) CD-derived native ECM mimics the transduction cascade initiated by purified collagen to (ii) the excessive deposition of collagen in the chronically inflamed CD mucosa and lamina propria, we propose the following central hypothesis: During the continuous remodeling of the ECM in IBD, a repair process quite distinct between UC and CD, engagement of select integrins on mucosal T cells modulates and potentially disrupts their signaling and function, thus contributing to chronicity and recurrence of the inflammatory process. This hypothesis will be tested by two specific aims: Aim 1. Molecular: Define the signaling pathways engaged by alternate ECM receptors that regulate LPT cytoskeletal rearrangement with a particular focus on the Rho family of small GTPases. Aim 2. Biochemical: Evaluate the specific protein serine kinases and target proteins modulated by the ligation of distinct integrin molecules in the migratory LPT, with a particular focus on vimentin.

溃疡性结肠炎（UC）的组织损伤主要是上皮及其基底膜的溃疡。相反，克罗恩病（CD）的特征在于固有层、粘膜肌层、粘膜下层、固有肌层和浆膜中纤维状胶原的过度沉积。因此，在两种形式的炎症性肠病（IBD）中，组织重塑以及小肠的破坏和恢复是导致解剖学破坏和主要临床后果的持续和动态过程。在粘膜T淋巴细胞陷入蛋白质，糖蛋白和蛋白多糖称为细胞外基质（ECM）的复杂和高度组织化的网络中，我们提出IBD的慢性化，恶化和复发是多因素的，涉及混合的致病性T细胞对组织损伤和纤维化产生不利影响的过程，反之亦然。我们发表的和初步的结果表明，整合素介导的粘附到ECM是一个中心事件，在产生的免疫反应。因此，我们推测ECM粘附和辅助功能也是调节IBD的关键机制。我们报告说，胶原蛋白在效应/记忆T细胞启动的信号转导途径是不同的纤连蛋白启动。此外，小GTP酶的Rho家族成员，其调节细胞骨架重组，在粘附于纤连蛋白的T细胞中活化，与T细胞结合于胶原时活化的不同，并且波形蛋白（T细胞中中间丝的关键组分）的头部结构域上的丝氨酸磷酸化模式也类似地不同。我们还表明，一个三维的，天然ECM合成的人肠成纤维细胞（HIF）从控制患者启动T细胞中的信号转导级联反应不同的启动由HIF分泌的天然基质从克罗恩病患者。当我们将（i）CD衍生的天然ECM模拟由纯化的胶原蛋白引发的转导级联与（ii）胶原蛋白在慢性炎症CD粘膜和固有层中的过度沉积的观察结果结合起来时，我们提出了以下中心假设：在IBD中ECM的持续重塑过程中，UC和CD之间的修复过程非常不同，粘膜T细胞上选择的整联蛋白的参与调节并潜在地破坏它们的信号传导和功能，从而导致炎症过程的慢性化和复发。这一假设将通过两个具体目标来检验：目标1。分子：定义由调节LPT细胞骨架重排的替代ECM受体参与的信号通路，特别关注小GTP酶的Rho家族。目标2.生化：评估特定的蛋白丝氨酸激酶和靶蛋白调节不同的整合素分子的连接在迁移性LPT，特别是对波形蛋白。