Trefoil factor proteins regulate inflammation and immunity

&RQWDFW 3‘3，+HUEHUW’HEURVNL 5 项目总结 在正常情况下，由磨损、化学物质或生物制剂引起的粘膜组织损伤 迅速解决，以免持续的炎症反应导致慢性病。然而，基本的 了解黏膜界面的免疫调节和再生机制 仍然是支离破碎和不清楚的。这个UO1项目的中心目标是揭示三叶因子家族是如何 (TFF)蛋白保护胃肠道(GI)免受损伤性炎症反应并驱动宿主 对后生动物寄生虫和病原菌的保护。初步数据显示，我们有 发现了一类以前未知的TFF2和TFF3受体，这一发现与 影响细胞和分子理解三叶因子在免疫细胞中的反应性如何 控制耐受性和炎症之间的平衡。事实上，我们证明了这种治疗方法 给予TFF3可缓解结肠炎，暴露TFF3可促进白细胞介素10家族 人和小鼠免疫细胞分泌细胞因子。综上所述，这一计划的总体目标是 该项目旨在为三叶因子生物学领域带来概念和技术上的进步。我们的两个 主要问题是：(1)三叶因子是否通过同源受体-配体相互作用发挥作用 富含亮氨酸重复序列和Ig结构域的成员，包含Nogo受体相互作用蛋白(LINGO) 家族和(2)三叶因子是否在结肠炎或结肠炎的情况下严重影响粘膜免疫反应 病原体感染通过调节白介素10家族细胞因子的产生。我们的中心假设是 三叶因子3通过依赖LINGO受体调节粘膜IL-10和IL-22的产生 机械装置。特定目标1的实验将确定TFF3是否通过LINGO2和/或 LINGO_3依赖的机制，那些在特定目标2中定义的途径(S)和生物学重要性 对于依赖TFF3的IL-10的产生和特定目的的实验3将定义细胞和分子 TFF3调节IL-22的机制(S)。通过成功完成我们的项目目标，我们 意在激发人们对三叶因子的广泛兴趣和合作研究，将其作为 在粘膜界面形成免疫、炎症和修复的机制。 3URMHFW 6XPPDU\$EVWUDFW 3DJH

&RQWDFW 3'3, +HUEHUW 'HEURVNL 5 PROJECT SUMMARY Under normal circumstances, mucosal tissue damage caused by abrasions, chemicals, or biological agents is quickly resolved, lest persistent inflammatory responses drive chronic disease. However, the basic understanding of the immunoregulatory and regenerative mechanisms operating at the mucosal interface remains fragmented and unclear. The central goal of this UO1 project is to uncover how Trefoil factor family (TFF) proteins protect the gastrointestinal (GI) tract from injurious inflammatory responses and drive host protection against metazoan parasites and pathogenic bacteria. Preliminary data shows that we have discovered a previously unknown class of receptors for TFF2 and TFF3, a finding that stands to radically impact the cellular and molecular understanding of how Trefoil factor responsiveness in immune cells could govern the balance between tolerance and inflammation. Indeed, we demonstrate that therapeutic administration of TFF3 resolves colitic inflammation and that TFF3 exposure promotes interleukin 10 family cytokine secretion from both human and mouse immune cells. Taken together, the over-arching goal of this project is to bring forth a conceptual and technological advance to the field of Trefoil factor biology. Our two main questions are: (1) whether Trefoil factors function through cognate receptor-ligand interactions with members of the Leucine rich repeat and Ig domain containing, Nogo receptor interacting protein (LINGO) family and (2) whether Trefoil factors critically influence mucosal immune responses in the context of colitis or pathogen infection through regulation of interleukin 10 family cytokine production. Our central hypothesis is that Trefoil factor 3 regulates mucosal IL-10 and IL-22 production through LINGO receptor-dependent mechanisms. Experiments in specific aim 1 will establish whether TFF3 suppresses colitis via LINGO2 and/or LINGO3-dependent mechanisms, those in specific aim 2 will define the pathway(s) and biological importance for TFF3-dependent IL-10 production and experiments in specific aim 3 will define the cellular and molecular mechanism(s) for TFF3-mediated regulation of IL-22. Through successful completion of our project goals, we intend to stimulate broad interest and collaborative investigation of Trefoil factors as an important part of the mechanisms that shape immunity, inflammation, and repair at the mucosal interface. 3URMHFW 6XPPDU\$EVWUDFW 3DJH