INTESTINAL ADENOSINE A2B RECEPTOR

肠腺苷 A2B 受体

• 批准号: 6700597
• 负责人: SHANTHI Vasudevan SITARAMAN
• 金额: $ 0.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700597
• 关键词: G protein; Salmonella typhimurium; biological signal transduction; cell cell interaction; cellular polarity; chlorine; gastrointestinal epithelium; human subject; inflammation; interleukin 8; neutrophil; purine /pyrimidine metabolism; purinergic receptor; receptor expression; secretion; tissue /cell culture; transfection; tumor necrosis factor alpha

DESCRIPTION (adapted from the application) The overall aim of this project is to better define the characteristics of intestinal epithelial cell-neutrophil interaction as it relates to fluid and electrolyte secretion. Many intestinal disorders, particularly the acute flare of inflammatory bowel disease (IBD), are characterized by migration of neutrophils across the intestinal epithelium into the lumen to form 'crypt abscess'. Crypt abscesses are pathognomic of active IBD and infectious colitis and correlate with severity of disease as well as clinical symptoms. We have previously shown that neutrophil migration into the intestinal lumen elicits electrogenic chloride secretion (secretory diarrhea) and the major effector of this chloride secretory response is the neutrophil-derived secretagogue, 5'AMP. Intestinal epithelia express an ectonucleotidase, which converts 5' AMP to adenosine which then interacts with intestinal epithelial adenosine 2b (A2b) receptor to elicit chloride secretion. Thus the A2b receptor plays a central role in orchestrating chloride secretion induced by neutrophils. An understanding of the regulation and signaling mechanism of A2b receptor may therefore lead to designing of novel treatments for this component of IBD. In this proposal, I intend to characterize the biology of intestinal A2b receptor using two intestinal epithelial cell models: T84 cells and Caco-2 bbe cells transfected with the A2b receptor. A2b receptor is the only adenosine receptor in T84 cells while Caco-2 bbe cells lack A2b receptor. First, I will study the polarity of surface expression, distribution, kinetics of turnover, structural requirements for ligand binding, desensitization, and G-protein recognition. Second, I will analyze the existence of ectonucleotidase and A2b receptor in signaling membrane microdomain such as caveolae. These microdomains represent invagination of plasma membrane enriched in glycosphingolipid, which have been shown to contain signaling proteins. Third, I will study the role of adenosine receptor in the modulation and feedback regulation of neutrophil-epithelial interaction including transmigration and chemokine secretion.

描述（改编自应用程序） 该项目的总体目标是更好地界定 肠上皮细胞-中性粒细胞相互作用，因为它涉及流体和 电解质分泌许多肠道疾病，特别是急性发作 炎症性肠病（IBD）的特征是 嗜中性粒细胞穿过肠上皮进入肠腔，形成“隐窝 是的。隐窝扩张是活动性IBD和感染性结肠炎的病理特征 并与疾病的严重程度以及临床症状相关。我们有 先前表明，中性粒细胞迁移到肠腔， 产电性氯化物分泌（分泌性腹泻）和 这种氯化物分泌反应是嗜中性粒细胞衍生的促分泌素，5 ′ AMP。 肠上皮细胞表达外核苷酸酶，其将5' AMP转化为 然后与肠上皮腺苷2b（A2 b）相互作用的腺苷 受体以引起氯化物分泌。因此，A2 b受体起着中枢作用。 在协调中性粒细胞诱导的氯化物分泌中的作用。一个 了解A2 b受体的调节和信号传导机制， 因此导致设计针对IBD的该组分的新治疗。在 这个建议，我打算表征肠道A2 b受体的生物学特性 使用两种肠上皮细胞模型：T84细胞和Caco-2 bbe细胞 用A2 b受体转染。A2 b受体是唯一的腺苷受体 而Caco-2 bbe细胞缺乏A2 b受体。首先，我将研究 表面表达的极性，分布，转换动力学，结构 需要配体结合、脱敏和G蛋白识别。 第二，我将分析外核苷酸酶和A2 b受体的存在， 信号传导膜微结构域如小窝。这些微区代表了 富含鞘糖脂的质膜内陷， 显示含有信号蛋白。第三，研究腺苷的作用 受体在嗜中性粒细胞-上皮细胞调节和反馈调节中的作用 相互作用包括迁移和趋化因子分泌。