Role of ghrelin in intestinal inflammation

胃饥饿素在肠道炎症中的作用

• 批准号: 7246554
• 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/7246554
• 关键词: Acute; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Binding; Biological Assay; Cells; Chronic; Clostridium difficile; Clostridium difficile tcdA protein; Clostridium enterotoxin; Colitis; Colon; Communication; Condition; Crohn' s disease; DNA; Data; Desire for food; Development; Eating; Endocrine; Endocrine Gland Neoplasms; Endothelial Cells; Epithelial Cells; Experimental Models; Fluids and Secretions; Functional disorder; Gastric Acid; Gastric Emptying; Gene Expression; Genus Cola; Goals; Healed; Histopathology; Hormones; Human; IL8 gene; Immune system; Immunohistochemistry; In Situ Hybridization; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-1; Interleukin-6; Interleukin-8; Intestinal Mucosa; Intestines; Label; Large Intestine; Ligands; Liquid substance; Literature; Mediator of activation protein; Messenger RNA; Metabolic; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mucous Membrane; Mus; NF-kappa B; Neuraxis; Obesity; Organism; Pathway interactions; Patients; Peptides; Peripheral; Pituitary Gland; Play; Process; Proteins; Radio; Rattus; Receptor Gene; Reverse Transcriptase Polymerase Chain Reaction; Role; Score; Severities; Small Intestines; Somatotropin; Stimulus; Stomach; Sulfonic Acids; System; Testing; Toxin; biological adaptation to stress; cytokine; design; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; healing; in vivo; increased appetite; insight; novel; receptor; receptor expression; research study; response; sym-trinitrobenzene; transcription factor

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信对于控制生物体对炎症刺激的反应很重要。 Ghrelin是一种新确定的有效的生长激素秘密，是一种独特的酰化28氨基酸肽，主要是从胃中分泌的，并进入中枢神经系统，在中枢神经系统中刺激了垂体中的生长激素释放。生长素还可以增加食欲和食物摄入量并刺激肥胖症。生长素蛋白及其受体在动物和人类的胃，小肠和结肠以及胃和肠内内分泌肿瘤中表达。生长素蛋白刺激胃酸分泌，并加速胃排空和液态餐的小肠道转运。但是，尚无有关生长素是否参与系统性或肠炎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（Crohn's氏病的动物模型）中，生长素蛋白及其受体（GHS-R）基因的表达显着上调。此外，使用大鼠和人肠细胞，我们表明，生长素蛋白与其受体的结合会导致MAP激酶和NF-kappab激活，并刺激白介素-8的表达，这是中性粒细胞的有效趋化因子。这些结果开辟了一个可能性，除了其培训和代谢作用外，生长素还可能在炎症过程中起重要作用。我们的假设是，周围生长素释放蛋白通过与其在肠道中的特定受体结合和转录因子Kappab的激活来增强肠炎。该提案的总体目标是研究生长素蛋白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AIM 1中，我们将在不同的肠炎模型中表征生长素蛋白及其受体的表达，并鉴定出在肠粘膜中表达这些分子的细胞。 AIM 2将检查生长素素和生长素释放蛋白受体拮抗作用是否会改变体内肠道炎症的发展。 AIM 3中的实验将确定NF-kappab途径在生长素蛋白诱导的IL-8基因表达中的作用，并检查与生长素蛋白诱导的NF-kappab激活相关的上游途径。了解生长素蛋白在肠道炎症中的作用以及刺激IL-8等炎症细胞因子表达的分子机制，将为人类炎症性肠病（IBD）以及可能其他炎症状况的病理生理提供重要的见解。