Extracellular Matrix in Inflammatory Bowel Disease

炎症性肠病中的细胞外基质

• 批准号: 7741313
• 负责人: Alan David Levine
• 金额: $ 36.32万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741313
• 关键词: Actins; Adhesions; Adhesives; Adverse effects; Affect; Amino Acids; Anatomy; Area; 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; Constipation; Crohn' s disease; Cytoskeletal Modeling; Cytoskeleton; DNA Sequence Rearrangement; Data; Deposition; Diarrhea; Disease; ECM receptor; 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; 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; Reporting; Research; Research Personnel; Rest; Role; Serine; Serous Membrane; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Intestines; Structure; Submucosa; System; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tyrosine Phosphorylation; Ulcer; Ulcerative Colitis; Vimentin; biological systems; cell motility; design; imprint; interstitial; member; migration; peripheral blood; polymerization; receptor-mediated signaling; repaired; response; rho; rho GTP-Binding Proteins

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）的特点是纤维性胶原在固有层、粘膜肌层、粘膜下层、固有肌层和浆膜中过度沉积。因此，在两种形式的炎症性肠病（IBD）中，组织重塑以及间质的破坏和恢复是持续和动态的过程，有助于解剖破坏和主要临床后果。粘膜T淋巴细胞被包裹在复杂且高度组织化的蛋白质、糖蛋白和蛋白聚糖网络中，被称为细胞外基质（ECM），我们认为IBD的慢性、加重和复发是多因素的，涉及混合致病性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。我们发表的初步结果表明，整合素介导的ECM粘附是产生免疫反应的中心事件。因此，我们假设ECM的粘附和附属功能也是调节IBD的关键机制。我们报道了在效应/记忆T细胞中由胶原蛋白启动的信号转导途径不同于由纤维连接蛋白启动的信号转导途径。此外，调节细胞骨架重组的小gtpase的Rho家族成员，在附着于纤维连接蛋白的T细胞中被激活，与当T细胞与胶原结合时被激活的Rho家族成员不同，并且vimentin （T细胞中中间纤维的关键成分）头部结构域的丝氨酸磷酸化模式也同样不同。我们还证明，由对照患者的人肠成纤维细胞（HIF）合成的三维天然ECM在T细胞中启动信号转导级联，不同于由克罗恩病患者的HIF分泌的天然基质启动的信号转导级联。当我们观察到(i) CD来源的天然ECM模拟纯化胶原引发的转导级联（ii）慢性炎症的CD粘膜和固有层中胶原的过度沉积时，我们提出以下中心假设：在IBD中ECM的持续重塑过程中，UC和CD之间的修复过程截然不同，选择整合素参与粘膜T细胞调节并可能破坏其信号传导和功能，从而导致炎症过程的慢性和复发。这一假设将通过两个具体目标来检验：目标1。分子：定义调节LPT细胞骨架重排的替代ECM受体所参与的信号通路，特别关注小gtpase的Rho家族。目标2。生化：评估特定的蛋白丝氨酸激酶和目标蛋白通过连接不同的整合素分子在迁移的LPT，特别关注波形蛋白。