Mucosal organs such as the intestine and lung are highly vascular ograns with extensive metabolic demands, and for this reason, are particularly susceptible to diminished blood flow and resultant tissue hypoxia. Epithelial cells which line mucosal organs function to orchestrate a multitude of mucosal responses, and given their anatomic location, are primary targets for hypoxia-mediated damage. Previous studies have explored the response of epithelial and endothelial cells to ambient hypoxia and these studies defined a transcriptional signaling pathway mediated by the intracellular messenger cyclic AMP, and specifically by the transcriptional co-activator cAMP response element binding protein (CREB). At present, it is unclear how hypoxia activates CREB-mediated transcriptional responses, but significant preliminary data indicate that hypoxia selectively activates a number of pro-inflammatory genes in a CREB-dependent fashion. In this proposal, they will test the hypothesis that specific transcriptional events mediated by CREB coordinate epithelial responses to hypoxia. As such, three specific aims are proposed to test this hypothesis. First, they will elucidate the molecular pathway(s) of hypoxia-regulated CREB activation. We will utilize extensive in vitro and in vivo models to answer basic questions regarding CREB regulation, turnover, and signaling. Second, they will explore the impact of hypoxia on epithelial barrier function. As such, they will elucidate the cooperative contributions of CREB and hypoxia-inducible factor-1-mediated regulation of epithelial junctional permeability during hypoxia in vitro and in vivo. Third, they will examine the molecular events of leukocyte trafficking across intestinal epithelial cells. In particular, they will emphasize CREB-regulated surface molecules which orchestrate leukocyte transit through the mucosa. The overall aim of this proposal is to elucidate the transcriptional signaling events mediating mucosal epithelial responses to hypoxia and inflammation.
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