TAM receptor tyrosine kinases in inflammatory boweldisease

TAM 受体酪氨酸激酶在炎症性肠病中的作用

基本信息

批准号：
8816712
负责人：
Carla Rothlin
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816712
关键词：
Ablation Agonist Anti-Inflammatory Agents Anti-inflammatory Biochemical CISH gene Cells Chronic Colitis Data Development Disease Disease remission Ensure Excision Family Fistula Funding Gastrointestinal tract structure Genetic Health Homeostasis Human Immune Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Injury Interleukin-10 Interleukin-4 Intervention Intestinal Fibrosis Intestinal Mucosa Intestines Knowledge Ligands Mediating Modeling Molecular Mus Myeloid Cells Natural regeneration Organ Pathway interactions Phase Phenotype Physiological Population Production Protein S Punch Biopsy Radio Receptor Protein-Tyrosine Kinases Relapse Resistance Resolution Role Shapes Signal Pathway Signal Transduction Sodium Dextran Sulfate T-Lymphocyte Testing Therapeutic Tissues Tumor Necrosis Factor-alpha Ulcer Wound Healing base cell type combinatorial cytokine design efficacy testing improved inhibitor/antagonist macrophage mouse model novel programs receptor response response to injury tissue regeneration tissue repair translational study type I interferon receptor

项目摘要

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are relapsing disorders of the gastrointestinal tract characterized by chronic inflammation of the intestinal mucosa and tissue damage. Current pharmacological approaches in IBD primarily focus on dampening the inflammatory immune response. However, IBD is often associated with deficient or pathological tissue repair such as ulcers or fistulas and intestinal fibrosis or strictures. Therefore, understanding the mechanisms that promote tissue repair and physiological regeneration of the intestine is of outstanding importance towards the development of improved therapies in IBD. Macrophages have a fundamental role in inflammation as well as in tissue repair. While classically activated macrophages (M1) predominate during inflammation, the resolution of inflammation and intestinal wound healing is dependent on the transition of macrophages into an alternative, tissue repair (M2) state. We propose that the Axl and Mer (AM) receptor tyrosine kinases coordinate the phasing out from the M1 with the induction of the M2 response. We propose to (i) identify the molecular mechanism by which AM RTK signaling induces M2-macrophage polarization, (ii) identify the intestinal macrophage population in which the AM RTK signaling pathway coordinates the M1 to M2 switch to limit inflammation and induce tissue repair in the gut, and (iii) validate the AM pathway as a novel target for the combinatorial suppression of inflammation and induction of tissue repair in mouse models of injury in the gut. Unraveling the mechanism by which the AM pathway shapes macrophage polarization, ensuring effective silencing of the inflammatory state, together with the induction o the tissue repair program and obtaining proof-of-concept for engaging the AM RTKs in mouse models of intestinal injury will (1) significantly advance our knowledge on mucosal homeostasis and (2) pave the way for translational studies towards new and improved treatments in IBD.

描述（由申请人提供）：炎症性肠病（IBD）是胃肠道的复发性疾病，其特征是肠粘膜慢性炎症和组织损伤。 IBD中当前的药理学方法主要集中在减弱炎症免疫反应。但是，IBD通常与缺乏或病理组织修复有关，例如溃疡，瘘管以及肠纤维化或狭窄。因此，了解促进肠道组织修复和生理再生的机制对于改善IBD疗法的发展至关重要。巨噬细胞在炎症以及组织修复中具有基本作用。虽然在炎症期间，经典活化的巨噬细胞（M1）占主导地位，但炎症和肠道伤口愈合的分辨率取决于巨噬细胞向替代的组织修复（M2）状态的过渡。我们建议AXL和MER（AM）受体酪氨酸激酶与M2响应诱导从M1划分。我们提出（i）确定AM RTK信号传导诱导M2巨噬细胞极化的分子机制，（ii）确定AM RTK信号通路在其中M1至M2的AM RTK信号途径在其中限制了炎症并限制了肠道和（III II）的组合物，并限制了M2的切换，以限制炎症和（III）的组合。在肠道损伤模型中修复。 Unraveling the mechanism by which the AM pathway shapes macrophage polarization, ensuring effective silencing of the inflammatory state, together with the induction o the tissue repair program and obtaining proof-of-concept for engaging the AM RTKs in mouse models of intestinal injury will (1) significantly advance our knowledge on mucosal homeostasis and (2) pave the way for translational studies towards new and improved treatments in IBD.