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.

项目摘要肠易激综合征 (IBS) 亚群中经常观察到内脏过敏临床研究表明，许多此类患者的发病机制尚不清楚。显示粘膜炎症的亚临床症状，并伴有肠道通透性增加。因此可以想象，粘膜屏障功能受损可能会促进抗原增加呈递给粘膜下层的免疫细胞，导致肥大细胞发生炎症。通过产生促炎剂和疼痛，在先天免疫防御中发挥重要作用我们的初步数据表明，resolvins 是一种新型介质，可能会引起内脏过敏。源自 omega-3 多不饱和脂肪的一类内源性抗炎脂质介质酸，存在于结肠粘膜中，在调节粘膜下肥大细胞中发挥重要作用此外，我们的临床研究表明，在 IBS-D 中。肠道菌群失调的患者，结肠分解素 D1 (RvD1) 水平显着降低我们还观察到，消退素缺陷小鼠表现出以下症状：我们研究的目的是 1. 调查功能关系。结肠组织中的分解素水平与内脏机械敏感性之间的关系；以及 2. 检查消退素抑制粘膜炎症和减少内脏炎症的机制我们发现结肠组织中的 RvD1 水平调节内脏。我们进一步提出 RvD1 机械地控制肥大细胞激活和促炎介质的合成，并降低感觉神经元的兴奋性，防止 RvD1 的这些有益作用是通过介导的。甲酰肽受体 2 (FPR2)/Gαi 减少 cAMP 形成的作用为了检验这一假设，我们有 3 个具体目标：目标 1：使用 2 种啮齿动物模型，其中结肠 RvD1 水平通过以下因素调节：分别是饮食因素和肠道微生物群，我们的目的是证明 RvD1 水平在结肠组织在调节内脏机械敏感性中发挥重要作用；目标2：在体内展示；在体外，RvD1 抑制肥大细胞脱颗粒并预防粘膜下炎症目标 3：证明 RVD1 调节通过激活 FPR2 受体，保护肠道 DRG 神经元的兴奋性，进而降低这些研究的结果将支持使用消解素作为一类药物。减少IBS患者粘膜下炎症和疼痛的新型治疗药物。