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.

项目总结