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.
