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，这是公认的。在过去的资金期间产生的结果首次证明了41个AA肽皮质激素释放激素（CRH），该激素（CRH）是在肠道中局部发行的，是一种有效的急性肠道肠道介导不同病情的急性肠道炎症。我们还对人类结肠细胞的熊受体进行了新的观察，这些受体在体内和暴露于艰难梭菌毒素A或促进性细胞因子后体内和体外肠道炎症期间被上调。我们的总体假设是，周围CRH和与CRN相关的肽尿素素通过与肠细胞和巨噬细胞上的特定CRH受体结合来增强急性结肠炎症。促炎转录因子和MAP-激酶 - 相关途径的CRH和泌尿诺素 - ddpentent激活导致促炎细胞因子的释放，从而启动增加肠道炎症。在AIM 1中，我们将阐明NF-kappab/kappab系统的参与以及MAP激酶在人类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，我们还将研究益生菌在毒素A和促炎细胞因子中的作用 - 在体外和体内诱导的CRH受体表达增加。 AIM 2中的研究将确定CRH家族在野生型和CRH受体缺乏小鼠中的小鼠回肠环中急性肠炎中的CRH家族（尿素素I，II和III）的作用，以及在 与人类肠内异种移植物中的Allan Walker博士（异种移植核）合作。与贝丝·麦考密克（Beth McCormick）博士合作，我们还将评估其他常见的胃菌细菌和细菌产物（沙门氏菌，志贺氏菌，LPS）对人体和体外人类结肠细胞中CRH肽家族和CRH受体表达的影响。 AIM 3将检查促炎细胞因子和艰难梭菌毒素A中CRH受体调节的机制。 CRH +/ +和CRH - / - 小鼠中的结肠细胞）和体内。拟议的研究的结果将有助于我们剖析MECHAMSM（S），CRH肽及其受体会参与肠炎。