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

描述(申请人提供)：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，但治疗性免疫干预的分子靶点仍然难以捉摸。肠道树突状细胞(DC)和巨噬细胞(Mφ，S)在介导黏膜耐受和抑制炎症中起着关键作用。在IBD中，这些细胞失去耐受性，导致失控的肠道炎症。然而， 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。我们发现了β-连环蛋白信号通路作为肠道DC和MφS耐受表型的关键分子调节因子的新的和先前未知的作用。β-连环蛋白位于肠道中广泛表达的三组配体(TLRL配体、WNT配体和E-钙粘蛋白)的下游，在这些细胞中去除β-连环蛋白会导致耐受性的丧失。目前的建议将集中在β-连环蛋白通路在调节关键下游效应机制中的机制作用，并在结肠炎和口服耐受的活体模型中测试其相关性。本研究的具体目标是：(1)了解β-catenin/Tcf通路调节肠道DC和M-φS(目标1)中三个关键免疫调节基因--IL-10、RALDH和IDO-的表达的分子机制；(Ii)了解该通路在肠道DC和MφS调节T细胞分化和扩增中的功能和生物学作用(目标2)，以及(Iii)它们抑制肠道炎症和促进口服耐受(目标3)的能力。这项拟议研究的成功完成将为肠道DC和MβφS如何调节耐受和炎症反应之间的平衡提供新的机制见解，并将为该途径在炎症性疾病中的靶向提供机制基础。β-连环蛋白途径的药理激活剂已经存在，而且更多的正在开发中，拟议的研究将为开发一类全新的药物提供理论基础，这些药物可能对治疗炎症性肠病具有重要的治疗作用。

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 (Mφs) 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 β-catenin signaling pathway as a key molecular regulator of tolerogenic phenotype in intestinal DCs and Mφs. β-catenin is downstream of three sets of ligands widely expressed in the gut (TLR ligands, wnt ligands and E-cadherin), and ablation of β-catenin in these cells causes loss of tolerance. The current proposal will focus on the mechanistic role of the β-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 β-catenin/TCF pathway regulates the expression of three key immune regulatory genes - IL-10, RALDH and IDO - in intestinal DCs and Mφs (Aim 1), (ii) to understand the functional and biological role of this pathway in intestina DCs and Mφs 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 β-catenin/TCF pathway in intestinal DCs and Mφs regulates a balance between tolerance and inflammatory responses, and will provide a mechanistic rationale for targeting this pathway in IBD. Pharmacological activators of β-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.