Trefoil factor proteins regulate inflammation and immunity

三叶因子蛋白调节炎症和免疫

• 批准号: 9170097
• 负责人: De'Broski R Herbert
• 金额: $ 47.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170097
• 关键词: Affinity; Amino Acids; Automobile Driving; Biological; Biological Products; Biology; Blood; Cancerous; Cell Lineage; Cells; Chemicals; Chromosome Structures; Chronic Disease; Colitis; Data; Dose; Epithelial Cells; Equilibrium; Family; Family member; Gastrointestinal tract structure; Generations; Goals; Human; Immune; Immune system; Immunity; Immunology; Infection; Inflammation; Inflammatory Response; Interleukin-1 beta; Interleukin-10; Interleukin-12; Intestines; Investigation; Lesion; Leucine-Rich Repeat; Ligands; Lymphocyte; Maps; Mediating; Modeling; Molecular; Mononuclear; Mucosal Immune Responses; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Nematoda; Nematode infections; Outcome; Parasites; Pathway interactions; Production; Protein Family; Proteins; Protozoa; RIPK1 gene; Regulation; Role; Shapes; Site; Sodium Dextran Sulfate; Source; Surface; T-Lymphocyte; TFF1 gene; Testing; Therapeutic; Ulcer; Work; cytokine; gastrointestinal; gastrointestinal infection; insight; interest; interleukin-22; macrophage; meetings; member; mouse model; mutant; novel; pathogen; pathogenic bacteria; receptor; regenerative; repaired; research study; transcription factor; trefoil factor

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.

项目概要 在正常情况下，由擦伤、化学物质或生物制剂引起的粘膜组织损伤是 迅速解决，以免持续的炎症反应导致慢性疾病。然而，基本的 了解粘膜界面的免疫调节和再生机制 仍然支离破碎且不明确。 UO1 项目的中心目标是揭示三叶因子家族如何 (TFF) 蛋白保护胃肠道 (GI) 免受有害炎症反应并驱动宿主 防止后生动物寄生虫和病原菌。初步数据显示，我们有 发现了一类以前未知的 TFF2 和 TFF3 受体，这一发现从根本上证明了这一点 影响细胞和分子对免疫细胞中三叶因子反应如何发挥作用的理解 控制耐受性和炎症之间的平衡。事实上，我们证明了治疗 TFF3 的施用可解决结肠炎炎症，并且 TFF3 暴露可促进白细胞介素 10 家族的产生 人类和小鼠免疫细胞分泌细胞因子。总而言之，本次活动的总体目标 该项目旨在为三叶因子生物学领域带来概念和技术进步。我们两个 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或结肠炎背景下的粘膜免疫反应 通过调节白细胞介素 10 家族细胞因子的产生来抑制病原体感染。我们的中心假设是 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。具体目标 1 的实验将确定 TFF3 是否通过 LINGO2 和/或抑制结肠炎 LINGO3 依赖机制，具体目标 2 中的机制将定义途径和生物学重要性 对于 TFF3 依赖性 IL-10 生产和特定目标 3 中的实验将定义细胞和分子 TFF3 介导的 IL-22 调节机制。通过成功完成我们的项目目标，我们 旨在激发对三叶因子的广泛兴趣和合作研究，作为该研究的重要组成部分 形成免疫、炎症和粘膜界面修复的机制。