Role of ghrelin in intestinal inflammation

胃饥饿素在肠道炎症中的作用

• 批准号: 6858720
• 负责人: DEZHENG ZHAO
• 金额: $ 12.9万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858720
• 关键词: cell population study; gastrointestinal hormones; gene expression; ghrelin; histopathology; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; inflammation; inflammatory bowel diseases; interleukin 8; intestinal mucosa; intestines; laboratory mouse; molecular pathology; nuclear factor kappa beta; pathologic process; polymerase chain reaction; protein quantitation /detection; radioimmunoassay; receptor binding; somatotropin

DESCRIPTION (provided by applicant): Communication between the endocrine and immune system is important in controlling the organism's response to inflammatory stimuli. Ghrelin, a newly identified potent growth hormone secretagogue, is a unique acylated 28 amino-acid peptide that is secreted predominantly from the stomach and enters the central nervous system where it stimulates growth hormone release from the pituitary. Ghrelin also increases appetite and food intake and stimulates obesity. Ghrelin and its receptor are expressed in stomach, small intestine, and colon of animals and humans as well as in endocrine tumors of the stomach and intestine. Ghrelin stimulates gastric acid secretion, and accelerates gastric emptying and small intestinal transit of a liquid meal. However, no information exists on whether ghrelin participates in the pathophysiology of systemic or intestinal inflammation. Our preliminary evidence indicates that expression of ghrelin and its receptor (GHS-R) gene is dramatically upregulated during 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced colonic inflammation, an animal model of Crohn's Disease. Moreover, using rat and human intestinal cells we show that binding of ghrelin to its receptor causes MAP kinase and NF-kappaB activation, and stimulates expression of interleukin-8, a potent chemotactic factor for neutrophils. These results open up the possibility that apart from its orexigenic and metabolic effects, ghrelin may play an important role in inflammatory processes. Our hypothesis is that peripheral ghrelin augments intestinal inflammation via binding to its specific receptors in the intestine and activation of the transcription factor kappaB. The overall goal of this proposal is to study the role of ghrelin and its receptor in the development of intestinal inflammation and identify the molecular mechanisms whereby these molecules participate in the inflammatory process. In aim 1 we will characterize expression of ghrelin and its receptor in different models of intestinal inflammation, and identify the cells expressing these molecules in the intestinal mucosa. Aim 2 will examine whether ghrelin and ghrelin receptor antagonism alter the development of intestinal inflammation in vivo. Experiments in aim 3 will determine the role of the NF-kappaB pathway in ghrelin-induced IL-8 gene expression and examine the upstream pathways involved in ghrelin-induced NF-kappaB activation. Understanding the role of ghrelin in intestinal inflammation and the molecular mechanisms whereby it stimulates expression of inflammatory cytokines such as IL-8, will provide important insights into the pathophysiology of human inflammatory bowel disease (IBD), and possibly other inflammatory conditions.

描述（由申请人提供）： 内分泌和免疫系统之间的通讯对于控制机体对炎症刺激的反应非常重要。 Ghrelin 是一种新发现的有效生长激素促分泌剂，是一种独特的酰化 28 个氨基酸肽，主要从胃分泌并进入中枢神经系统，刺激垂体释放生长激素。生长素释放肽还能增加食欲和食物摄入量并刺激肥胖。生长素释放肽及其受体在动物和人类的胃、小肠和结肠以及胃和肠的内分泌肿瘤中表达。生长素释放肽刺激胃酸分泌，加速胃排空和流质食物的小肠转运。然而，没有关于生长素释放肽是否参与全身或肠道炎症的病理生理学的信息。我们的初步证据表明，在 2,4,6-三硝基苯磺酸 (TNBS) 诱导的结肠炎症（克罗恩病动物模型）过程中，生长素释放肽及其受体 (GHS-R) 基因的表达显着上调。此外，利用大鼠和人类肠道细胞，我们发现生长素释放肽与其受体的结合会引起 MAP 激酶和 NF-κB 激活，并刺激白细胞介素 8（中性粒细胞的一种有效趋化因子）的表达。这些结果表明，除了其促进食欲和代谢作用外，生长素释放肽可能在炎症过程中发挥重要作用。我们的假设是，外周生长素释放肽通过与其在肠道中的特定受体结合并激活转录因子 kappaB 来增强肠道炎症。该提案的总体目标是研究生长素释放肽及其受体在肠道炎症发展中的作用，并确定这些分子参与炎症过程的分子机制。在目标 1 中，我们将表征不同肠道炎症模型中生长素释放肽及其受体的表达，并鉴定肠粘膜中表达这些分子的细胞。目标 2 将检查生长素释放肽和生长素释放肽受体拮抗作用是否会改变体内肠道炎症的发展。目标 3 中的实验将确定 NF-kappaB 通路在 ghrelin 诱导的 IL-8 基因表达中的作用，并检查与 ghrelin 诱导的 NF-kappaB 激活相关的上游通路。了解生长素释放肽在肠道炎症中的作用及其刺激 IL-8 等炎症细胞因子表达的分子机制，将为了解人类炎症性肠病 (IBD) 以及可能的其他炎症性疾病的病理生理学提供重要见解。