Modulation of intestinal inflammation by A2b receptor

A2b 受体调节肠道炎症

• 批准号: 7276084
• 负责人: VASANTHA L KOLACHALA
• 金额: $ 5.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276084
• 关键词: Adenosine; Adenylate Cyclase; Affect; Biological; Cell Line; Cell membrane; Cells; Chloride Ion; Chlorides; Colitis; Cyclic AMP; Data; Diarrhea; Epithelial; Epithelial Cells; Epitopes; Event; Fibronectins; Goals; Human; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interferon Type II; Interleukin-6; Intestines; Ischemic Bowel Disease; Lead; Light; Maleimides; Mediating; Membrane; Messenger RNA; Metabolism; Molecular; Mus; Pathogenesis; Physiological; Play; Production; Protein Isoforms; Purinergic P1 Receptors; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sodium Dextran Sulfate; Tumor Necrosis Factor-alpha; Vesicle; cytokine; human TNF protein; novel; receptor; receptor expression; therapy design; trafficking

DESCRIPTION (provided by applicant): Adenosine is an endogenous primordial signaling molecule that has been established as an important modulator of physiological as well as inflammatory responses in human. Adenosine is produced during normal cellular metabolism but is highly up-regulated during intestinal ischemia and inflammation. In the intestine, adenosine has been shown to mediate key events such as chloride secretion (secretary diarrhea) and cytokine production, two important features of intestinal inflammation. The biological effects of adenosine are mediated by the intestinal adenosine 2b receptor (A2bR) and thus the A2bR plays a central role in the pathogenesis of IBD. Thus the overall goal of the present proposal is to characterize the regulation and trafficking of the A2bR and study the effect of A2bR antagonist on intestinal inflammation. In the first specific aim, the molecular mechanism underlying A2bR trafficking will be studied. My preliminary data indicates that the A2bR trafficks to the membrane via vesicles and N-ethyl maleimide attachment receptor (SNARE) proteins are involved in the recruitment of the A2bR. Native intestinal epithelial cell line and intestinal cells transfected with epitope tagged A2bR will be used to study the signaling events required for the recruitment and functional role of the A2b recruitment. In the second specific aim, the effect of Th-1 cytokines, IFN-gamma and TNF-alpha, on the regulation of A2bR expression, trafficking and signaling will be studied. In the third specific aim, the effect of specific A2bR antagonist on murine colitis will be examined. Thus, studies on the A2bR will lead not only to the understanding of intestinal inflammation but may lead to novel therapies for intestinal inflammatory disorders.

说明（由申请人提供）：腺苷是一种内源性原始信号分子，已被确定为人体生理学和炎症反应的重要调节剂。腺苷在正常细胞代谢过程中产生，但在肠缺血和炎症过程中高度上调。在肠道中，腺苷已被证明介导关键事件，如氯化物分泌（分泌性腹泻）和细胞因子产生，这是肠道炎症的两个重要特征。腺苷的生物学效应是由肠腺苷2b受体（A2 bR）介导的，因此A2 bR在IBD的发病机制中起核心作用。因此，本发明的总体目标是表征A2 bR的调节和运输，并研究A2 bR拮抗剂对肠道炎症的作用。在第一个具体目标中，将研究A2 bR运输的分子机制。我的初步数据表明，A2 bR通过囊泡和N-乙基马来酰亚胺附着受体（SNARE）蛋白参与A2 bR的招募。天然肠上皮细胞系和用表位标记的A2 bR转染的肠细胞将用于研究募集所需的信号传导事件和A2 b募集的功能作用。在第二个具体目标中，将研究Th-1细胞因子IFN-γ和TNF-α对A2 bR表达、运输和信号传导的调节的作用。在第三个具体目标中，将检查特异性A2 bR拮抗剂对鼠结肠炎的作用。因此，对A2 bR的研究不仅会导致对肠道炎症的理解，而且可能会导致肠道炎症性疾病的新疗法。