Elucidating the hypoxia-inducible factor (HIF-1) response in gut barrier dysfunction and distant organdamage is the overall objective of this proposal. The studies proposed in this grant will test the followingglobal hypothesis that persistence of the ischemia-induced HIF-1alpha response by intestinal bacteria andtheir products shifts the HIF-1alpha response from an adaptive/protective response to a potentiallymaladaptive/injurious one. Consequently, in this proposal, we will test the concept that the sustained HIF-1cc response in the gut acts as an effector in ischemia/reperfusion-mediated gut injury and the production ofgut derived factors, thereby playing a role in gut-induced distant organ damage. By providing potentiallyimportant mechanistic information on the pathogenesis of T/HS-induced gut injury, the results obtained fromour studies will help clarify key issues of the Center Grant's first global hypothesis, which is that gut-derivedfactors present in the mesenteric lymph of the ischemic gut contribute to distant organ injury. Additionally,the experiments proposed in our Specific Aims will contribute to the Center Grant's second major hypothesisby testing whether the resistance of proestrus female rats to T/HS-induced gut injury is associated with adifferential HIF-1 intestinal response and that the intestinal HIF-1 response to T/HS is. at least in part.modulated by sex hormones.
Aim 1 will elucidate the functional significance of l/R-mediated elevations ofintestinal HIF-1 in vivo as well as the role of intestinal bacteria in prolonging the intestinal HIF-1 response.The effects of T/HS-induced gut injury, gut inflammation and acute lung injury will be examined in partiallydeficient HIF-1alpha+/- and HIF-1+/+ WT mice. To further evaluate the effect of intestinal bacteria on the HIF-1response, intestinal antibiotic decontamination and bacterial overgrowth male rat T/HS models will beemployed. The effects of partial HIF-1alpha deficiency on gut injury and inflammation will also be tested in theintestinal bacterial overgrowth and antibiotic decontaminated T/HS models.
Aim 2 will test whetheroverexpression or inhibition of HIF-1 in enterocytic cell lines affects gut barrier function and gut inflammationutilizing enterocytic cell lines.
Aim 3 will elucidate the mechanisms by which enteric bacteria or LPS regulateHIF-1 activation in enterocytes under normoxic conditions. Specifically, experiments will determine whetherregulation of HIF-1 is via the activation of MARK, Akt or NO.
Aim 4 will test the hypothesis that theresistance of proestrus female rats to T/HS-induced gut injury is associated with a blunted intestinal HIF-1 aresponse. A deeper insight of the intestinal HIF-1 response will identify potential targets for therapeuticintervention at the onset of intestinal ischemia.
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