Regulation of Oral Tolerance and Intestinal Inflammation by Beta-catenin/TCF Path

Beta-catenin/TCF 路径对口服耐受性和肠道炎症的调节

• 批准号: 8688238
• 负责人: Santhakumar Manicassamy
• 金额: $ 32.63万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688238
• 关键词: Ablation; Antigen-Presenting Cells; Antigens; Automobile Driving; Biological; Biological Assay; Cell Differentiation process; Cells; Clinical; Colitis; Complex; Crohn' s disease; Data; Decision Making; Dendritic Cells; Development; E-Cadherin; Equilibrium; Family; Family member; Genes; Genetic; Immune; Immune system; Immunology; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intervention; Intestines; Knock-out; Lamina Propria; Ligands; Lithium Chloride; Mediating; Modeling; Molecular; Molecular Target; Mus; Pathologic; Pathway interactions; Phase; Phenotype; Play; Process; Property; Protein Isoforms; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Role; Signal Pathway; T-Lymphocyte; TCF Transcription Factor; TCF7L2 gene; Testing; Therapeutic; Transfection; Ulcerative Colitis; beta catenin; food antigen; in vivo; in vivo Model; insight; macrophage; member; novel; novel therapeutic intervention; oral tolerance; pathogen; programs; promoter; response; selective expression; transcription factor

DESCRIPTION (provided by applicant): Crohn's disease and ulcerative colitis (inflammatory bowel disease, IBD) are important clinical problems, but molecular targets for therapeutic immune intervention remain elusive. Intestinal dendritic cells (DCs) and macrophages (M?s) play a pivotal role in mediating mucosal tolerance and suppressing inflammation. In IBD, these cells lose their tolerogenic properties resulting in uncontrolled intestinal inflammation. However, the molecular pathways that program these cells to a tolerogenic state rather than to an inflammatory state are not known. We have identified a new and previously unsuspected role for the ¿-catenin signaling pathway as a key molecular regulator of tolerogenic phenotype in intestinal DCs and M?s. ¿-catenin is downstream of three sets of ligands widely expressed in the gut (TLR ligands, wnt ligands and E-cadherin), and ablation of ¿-catenin in these cells causes loss of tolerance. The current proposal will focus on the mechanistic role of the ¿-catenin pathway in regulating key downstream effector mechanisms, and test its relevance in in vivo models of colitis and oral tolerance. Specific aims in the current proposal are (i) to understand the molecular mechanisms by which ¿-catenin/TCF pathway regulates the expression of three key immune regulatory genes - IL-10, RALDH and IDO - in intestinal DCs and M?s (Aim 1), (ii) to understand the functional and biological role of this pathway in intestina DCs and M?s in T regulatory cell differentiation and expansion (Aim 2), and (iii) their ability to limit intestinal inflammation and promote oral tolerance (Aim 3). The successful completion of the proposed studies will provide new mechanistic insights into how the ¿-catenin/TCF pathway in intestinal DCs and M?s regulates a balance between tolerance and inflammatory responses, and will provide a mechanistic rationale for targeting this pathway in IBD. Pharmacological activators of ¿-catenin pathway already exist, and more are in development and the proposed studies will provide a rationale for the development of an entirely new class of agents that may have significant therapeutic impact in treating IBD.

描述（由申请人提供）：克罗恩病和溃疡性结肠炎（炎症性肠病，IBD）是临床上重要的问题，但治疗性免疫干预的分子靶点仍然难以捉摸。肠树突细胞（DC）和巨噬细胞（M？s）发挥着关键作用。在介导粘膜耐受性和抑制炎症方面，这些细胞失去了耐受性，导致肠道炎症失控。 将这些细胞编程为耐受状态而不是炎症状态的分子途径尚不清楚，我们已经确定了 ¿ 的一种新的且以前未曾怀疑过的作用。 -连环蛋白信号通路作为肠道 DC 和 M?s 耐受表型的关键分子调节剂。 -catenin 是肠道中广泛表达的三组配体（TLR 配体、wnt 配体和 E-钙粘蛋白）的下游，并且 ¿这些细胞中的连环蛋白会导致耐受性丧失。当前的提议将重点关注 ¿ 的机制作用。 -连环蛋白途径调节关键下游效应机制，并测试其在结肠炎和口服耐受体内模型中的相关性。当前提案的具体目标是（i）了解 ¿ -catenin/TCF 通路调节肠道 DC 和 M? 中三个关键免疫调节基因 - IL-10、RALDH 和 IDO 的表达（目标 1），(ii) 了解该通路在肠道中的功能和生物学作用DC 和 M?s 在 T 调节细胞分化和扩增中的作用（目标 2），以及 (iii) 它们限制肠道炎症和促进口服耐受的能力（目标 3）。拟议研究的成功完成将提供新的机制见解。进入如何 ¿肠道 DC 和 M?s 中的连环蛋白/TCF 途径调节耐受性和炎症反应之间的平衡，并将为 IBD 的药理学激活剂靶向该途径提供机制依据。 -连环蛋白途径已经存在，并且更多的途径正在开发中，拟议的研究将为开发一类全新的药物提供理论基础，该药物可能对治疗 IBD 具有显着的治疗作用。