CORTICOTROPHIN RELEASING FACTOR IN INTESTINAL INFLAMMATI

肠道炎症中的促肾上腺皮质激素释放因子

• 批准号: 7021989
• 负责人: CHARABABOS POTHOULAKIS
• 金额: $ 33.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-10-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021989
• 关键词: Clostridium; I kappa B beta; SCID mouse; bacterial toxins; biotherapeutic agent; corticotropin releasing factor; gastrointestinal epithelium; human fetus tissue; inflammation; laboratory mouse; macrophage; mitogen activated protein kinase; neuropeptide receptor; neuropeptides; nuclear factor kappa beta; receptor expression; transcription factor; xenotransplantation

It is well accepted that neuropeptides are important components of the intestinal inflammatory response. Results generated during the past funding period demonstrated for the first time that the 41 aa peptide corticotropin-releasing hormone (CRH), released locally in the gut, is a potent promflammatory mediator of acute intestinal inflammation of different etiologies. We also made the novel observation that human colonocytes bear receptors for CRH, and these receptors are upregulated during intestinal inflammation in vivo and in vitro after exposure to C. difficile toxin A or proinflamrmtory cytokines. Our overall hypothesis is that peripheral CRH and the CRN-related peptides urocortins augment acute colonic inflammation by binding to specific CRH receptors on enterocytes and macrophages. CRH and urocortin-ddpendent activation of proinflammatory transcription factors and MAP-kinase - related pathways lead to the release of proinflammatory cytokines thereby initiating of augmenting intestinal inflammation. In aim 1 we will elucidate the participation of the NF-kappaB/kappaB system and MAP kinases in CRH receptor-mediated proinflammatory signalling in human colonic epithelial cells and macrophages. In collaboration with Dr. Ciaran Kelly we will also examine the effect of probiotics in toxin A and proinflammatory cytokines - induced increased CRH receptor expression in vitro and in vivo. Studies in aim 2 will determine the role of the CRH family of peptides (urocortin I, II, and III) in acute intestinal inflammation in mouse ileal loops in wild type and CRH receptor deficient mice and, in collaboration with Dr. Allan Walker (xenograft core), in human intestinal xenografts. In collaboration with Dr. Beth McCormick we will also assess the effect of other common GI bacteria and bacterial products (Salmonella, Shigella, LPS) on the CRH peptide family and CRH receptor expression in human colonocytes in vivo and in vitro. Aim 3 will examine the mechanism(s) of CRH receptor regulation in intestinal epithelial cells and macrophages by proinflammatory cytokines and C. difficile toxin A. We will also study whether CRH and CRH-related peptides themselves regulate CRH receptor expression in vitro (macrophages and colonocytes) and in vivo in CRH +/+ and CRH -/- mice. Results from the proposed studies will help us dissect the mechamsm(s) by which CRH family of peptides and their receptors participate in intestinal inflammation.

神经肽是肠道炎症反应的重要组成部分。在过去的资助期间产生的结果首次证明，在肠道中局部释放的41 aa肽促肾上腺皮质激素释放激素（CRH）是不同病因的急性肠道炎症的有效促炎介质。我们还发现，人结肠细胞具有CRH受体，并且这些受体在体内和体外肠道炎症过程中暴露于C。艰难梭菌毒素A或促炎细胞因子。我们的总体假设是，外周CRH和CRN相关肽尿皮质素通过与肠细胞和巨噬细胞上的特异性CRH受体结合而增强急性结肠炎症。促炎转录因子和MAP激酶相关途径的CRH和尿皮质素依赖性激活导致促炎细胞因子的释放，从而引发肠道炎症加剧。在目标1中，我们将阐明NF-κ B/κ B系统和MAP激酶在人结肠上皮细胞和巨噬细胞中CRH受体介导的促炎信号传导中的参与。与Ciaran Kelly博士合作，我们还将在体外和体内研究益生菌在毒素A和促炎细胞因子诱导的CRH受体表达增加中的作用。目的2中的研究将确定CRH家族肽（尿皮质素I、II和III）在野生型和CRH受体缺陷小鼠的小鼠回肠袢中的急性肠道炎症中的作用，以及在 与Allan步行者博士（异种移植核心）合作，在人类肠道异种移植中。与Beth McCormick博士合作，我们还将评估其他常见GI细菌和细菌产物（沙门氏菌，志贺氏菌，LPS）对体内和体外人结肠细胞中CRH肽家族和CRH受体表达的影响。目的3探讨促炎细胞因子和C.艰难梭毒素A我们还将研究CRH和CRH相关肽本身是否在体外（巨噬细胞和结肠细胞）和CRH +/+和CRH -/-小鼠体内调节CRH受体表达。这些研究结果将有助于我们深入剖析CRH家族多肽及其受体参与肠道炎症的机制。