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Actions of Resolvins on Intestinal Inflammation and Pain

Resolvins 对肠道炎症和疼痛的作用

基本信息

批准号：
9973272
负责人：
Gintautas Grabauskas
金额：
$ 46.65万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973272
关键词：
Abdominal Pain Acids Afferent Neurons Analgesics Anti-Inflammatory Agents Antigen Presentation Biopsy Biopsy Specimen Cell Degranulation Cell Extracts Cell Line Cell physiology Cells Clinical Research Colon Cyclic AMP Data Development Diet Dietary Factors Dinoprostone Docosahexaenoic Acids Electrophysiology (science)Exhibits Exposure to FPR2 gene Fish Oils Germ-Free Histamine Homeostasis Human Hypersensitivity Immune Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Bowel Diseases Intestinal permeability Intracolonic Irritable Bowel Syndrome LOX gene Mechanical Stimulation Mechanics Mediating Mediator of activation protein Modeling Mucositis Mucous Membrane Mus Neurons Omega-3 Fatty Acids Pain Pathway interactions Patients Play Property Resistance Rodent Rodent Model Role Sensory Thresholds Signal Transduction Pathway Submucosa TNF gene TRPV1 gene Testing Therapeutic Agents Tissues Visceral base cytokine dysbiosis effective therapy experience gut microbiota immune function in vivo indium arsenide inflammatory disease of the intestine inhibitor/antagonist lipid mediator mast cell novel novel therapeutics patch clamp prevent receptor reconstitution

项目摘要

PROJECT ABSTRACT Visceral hypersensitivity is frequently observed in a subpopulation of irritable bowel syndrome (IBS) patients. The responsible mechanism is unclear. Clinical studies show that many of these patients display subclinical signs of mucosal inflammation accompanied by increased gut permeability. It is therefore conceivable that impaired mucosal barrier function may facilitate increased antigen presentation to the immune cells in the submucosa, resulting in inflammation. Mast cells been shown to play important roles in the innate immune defense by producing proinflammatory agents and pain mediators which may induce visceral hypersensitivity. Our preliminary data show that resolvins, a novel class of endogenous anti-inflammatory lipid mediators derived from omega-3 polyunsaturated fatty acids, are present in the colonic mucosa and play an important role in regulating submucosal mast cell function and modulating the sensory threshold. Furthermore, our clinical studies show that in IBS-D patients with gut dysbiosis, the level of colonic resolvin D1 (RvD1) is significantly reduced compared to that observed in healthy controls. We also observed that resolvin-deficient mice exhibit evidence of visceral hypersensitivity. The objectives of our studies are 1. to investigate the functional relationship between the level of resolvins in the colonic tissue and visceral mechanical sensitivity; and 2. to examine the mechanisms by which resolvins inhibit mucosal inflammation and reduce visceral hypersensitivity. We hypothesize that the level of RvD1 in the colonic tissue modulates visceral mechanical sensitivity. We further propose that RvD1 mechanistically controls mast cell activation and synthesis of proinflammatory mediators, and decreases the excitability of sensory neurons, preventing the development of visceral hypersensitivity. These beneficial actions of RvD1 are mediated through the action of formyl peptide receptor 2 (FPR2)/ Gαi to reduce cAMP formation. To test this hypothesis, we have 3 specific aims: Aim 1: Using 2 rodent models in which colonic RvD1 levels are modulated by dietary factors and gut microbiota, respectively, we aim to demonstrate that the levels of RvD1 in the colonic tissue play an important role in regulating visceral mechanical sensitivity; Aim 2: To show in vivo and in vitro that RvD1 inhibits the degranulation of mast cells and prevents submucosal inflammation and the development of visceral hypersensitivity. Aim 3: To demonstrate that RVD1 modulates the excitability of gut-protecting DRG neurons by activating the FPR2 receptor, which in turn reduces intracellular cAMP levels. Results from these studies will support the use of resolvins as a class of novel therapeutic agents to reduce submucosal inflammation and decrease pain in IBS patients.

项目摘要