Mucosal organs such as the intestine and lung are highly vascular organs with extensive metabolic demands. Epithelial cells which line the intestine function to orchestrate a multitude of mucosal responses, and given their anatomic location, are primary targets for diminished blood flow and resultant hypoxia-mediated damage. Our previous studies have explored the response of intestinal epithelial cells to hypoxia and these studies defined a transcriptional signaling pathway mediated by hypoxia-inducible factor (HIF). Activation of HIF results in the coordinated induction of a cluster of apically-localized, barrier protective gene products. In this proposal, we will test the hypothesis that HIF coordinates protective epithelial responses to hypoxia.
3 specific aims are proposed to test this hypothesis. First, we will utilize newly developed murine models which express intestinal specific loss and gain of HIF function to answer basic questions regarding HIF activation in health and during intestinal disease in vivo. Second, we will build on recent findings to explore the influence of adenine nucleotide metabolism and signaling in vitro and in vivo. In particular, we will study how apically-localized membrane adenine nucleotide ecto-enzymes and adenosine receptors contribute to the regulation of leukocyte-mediated barrier disruption during hypoxia. Third, we will define molecular events of leukocyte trafficking across intestinal epithelial cells as they relate to hypoxia. In particular, we will elucidate the molecular details of hypoxia-regulated surface molecules which orchestrate leukocyte transit across the apical membrane surface. 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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