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: 8547805
• 负责人: Santhakumar Manicassamy
• 金额: $ 31.48万
• 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/8547805
• 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（由适用提供）：克罗恩病和溃疡性结肠炎（炎症性肠病，IBD）是重要的临床问题，但是热免疫干预的分子靶标仍然难以捉摸。肠树突状细胞（DC）和巨噬细胞（M？s）在介导粘膜耐受性和抑制炎症中起关键作用。在IBD中，这些细胞失去了其耐受性特性，导致不受控制的肠炎。然而， 将这些细胞编程为耐受性态而不是炎症状态的分子途径尚不清楚。我们已经确定了� -Catenin信号通路的新作用，并且是肠道DC和M？s中耐受性表型的关键分子调节剂。 - 蛋白酶是在肠道中广泛表达的三组配体的下游（TLR配体，Wnt配体和e-钙粘着蛋白），在这些细胞中的»钙蛋白在这些细胞中的消融会导致耐受性丧失。当前的提案将重点介绍 - - 卡丁蛋白途径在调节下游效应器机制中的机械作用，并测试其在体内结肠炎和口服耐受模型中的相关性。 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），以及（iii）它们限制肠道注射和促进口腔耐受性的能力（AIM 3）。拟议的研究的成功完成将提供新的机械见解，以了解肠道DC中的 - 帕宁蛋白/TCF途径如何调节耐受性和炎症反应之间的平衡，并将提供针对IBD中这一途径的机械原理。 » - 加丁蛋白途径的药理学激活剂已经存在，并且正在开发中，并且拟议的研究将为开发一种全新的药物的发展提供理由，这些药物可能在治疗IBD方面具有重大的热影响。