Disruption of intestinal epithelial barrier occurs commonly in various critical surgical conditions, including sepsis, hemorrhage, massive surgical operation, trauma, and burns, and results in the translocation of bacteria and endotoxin into the blood stream. The exact mechanisms and agents that regulate intestinal epithelial barrier function are still obscure and effective therapies to prevent the barrier dysfunction are limited, contributing to death in critical surgical patients with gut barrier dysfunction. Natural polyamines are shown to play a critical role in maintenance of intestinal epithelial integrity, and the regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving epithelial cell functions. The cadherin-rich adherens junctions mediate strong cell-cell contacts and have functional role in forming and regulating epithelial barrier. We have recently demonstrated that polyamines modulate intercellular junctions in intestinal epithelial cells and that polyamine depletion decreases expression of adherens junctions, especially E-cadherin, which is associated with an increase in intestinal paracellular permeability. Preliminary studies further indicate that a) polyamines regulate expression of the E-cadherin gene primarily at the transcriptional level and b) inhibition of E-cadherin by SiRNA antisense disrupts intestinal epithelial barrier function. Based on these observations, we hypothesize that polyamines play an important role in regulation of intestinal epithelial barrier function by altering E-eadherin expression.
Three specific aims will be pursued to test the hypothesis. 1) To define the molecular mechanism by which polyamines regulate transcription of the Ecadherin gene in intestinal epithelial ceils. 2) To determine the role and mechanisms of polyamine-mediated Ecadherin in the regulation of intestinal epithelial paracellular permeability. 3) To determine the role polyamines in E-cadherin expression and barrier function during surgical stress in vivo and further elucidate changes in Ecadherin in patients with gut barrier dysfunction. Completion of these specific aims will provide novel information regarding the regulation of intestinal barrier, which may lead to the development of new therapeutic strategies. Because barrier dysfunction occurs commonly in critical surgical patients and contributes to death, the subject matter of this proposal is timely, important, and has direct clinical application.
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