Modulation of intestinal inflammation by A2b receptor

A2b 受体调节肠道炎症

• 批准号: 7000252
• 负责人: VASANTHA L KOLACHALA
• 金额: $ 4.83万
• 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/7000252
• 关键词: adenosine; biological signal transduction; cell line; colitis; cytokine; disease /disorder model; gastrointestinal epithelium; gastrointestinal pharmacology; helper T lymphocyte; inflammation; inflammatory bowel diseases; inhibitor /antagonist; interferon gamma; intestines; postdoctoral investigator; protein transport; purinergic receptor; receptor expression; transfection; tumor necrosis factor alpha

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.

描述（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，腺苷已被证明可以介导关键事件，如氯化物分泌（分泌性腹泻）和细胞因子的产生，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（A2bR）介导的，因此A2bR在IBD的发病机制中起核心作用。因此，本研究的总体目标是表征A2bR的调控和运输，并研究A2bR拮抗剂对肠道炎症的影响。在第一个具体目标中，将研究A2bR运输的分子机制。我的初步数据表明，A2bR通过囊泡运输到膜上，n -乙基马来酰亚胺附着受体（SNARE）蛋白参与了A2bR的募集。我们将利用转染A2bR表位的天然肠上皮细胞系和肠细胞来研究A2b募集所需的信号事件及其功能作用。在第二个特定目标中，将研究Th-1细胞因子，ifn - γ和tnf - α对A2bR表达，运输和信号传导的调节作用。在第三个特定目的中，将研究特异性A2bR拮抗剂对小鼠结肠炎的作用。因此，对A2bR的研究不仅将导致对肠道炎症的认识，而且可能导致肠道炎症性疾病的新疗法。