Trefoil factor proteins regulate inflammation and immunity

&RQWDFW 3'3，+HUEHUW 'HEURVNL 5 项目摘要 在正常情况下，由擦伤、化学品或生物制剂引起的粘膜组织损伤是不可避免的。 迅速解决，以免持续的炎症反应驱动慢性疾病。但其基本 了解在粘膜界面运作的免疫调节和再生机制 仍然是支离破碎和不明确的。这个UO 1项目的中心目标是揭示三叶因子家族如何 (TFF)蛋白质保护胃肠道（GI）免受有害的炎症反应， 防止后生动物寄生虫和致病细菌。初步数据显示， 发现了一种以前未知的TFF 2和TFF 3受体，这一发现从根本上证明了 影响了对免疫细胞中三叶因子反应性的细胞和分子理解， 控制着耐受和炎症之间的平衡。事实上，我们证明， 施用TFF 3解决结肠炎炎症，TFF 3暴露促进白细胞介素10家族 从人和小鼠免疫细胞分泌细胞因子。总的来说，这一过度的目标 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。我们两 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含有IG结构域的Nogo受体相互作用蛋白（LINGO）的成员 家族和（2）三叶因子是否严重影响结肠炎背景下的粘膜免疫应答， 病原体感染通过调节白细胞介素10家族细胞因子的产生。我们的核心假设是 三叶因子3通过LINGO受体依赖性调节粘膜IL-10和IL-22的产生， 机制等具体目的1中的实验将确定TFF 3是否通过LING 0 2和/或LING 2抑制结肠炎。 LINGO 3依赖性机制，具体目标2中的机制将定义途径和生物学重要性 对于TFF 3依赖性IL-10的产生，具体目标3中的实验将定义细胞和分子 TFF 3介导的IL-22调节的机制。通过成功完成项目目标，我们 旨在激发广泛的兴趣和三叶因子的合作研究作为一个重要组成部分， 形成免疫、炎症和粘膜界面修复的机制。 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