Ischemic stress is a central characteristic of a variety of pathologic conditions. Ischemic stress results from an imbalance of energy demands with associated supply during the ischemic phase, followed by the injury associated with reperfusion. While certain systems, particularly the cardiovascular system, have been studied in depth, little is understood about the cellular response to ischemic stress in intestinal epithelial cells. In this series of studies, we sought to describe the signaling that occurs in intestinal epithelial cells during ischemic stress.
Protein Kinase C is known to be important in signaling during ischemic stress in cardiomyocytes. In my first series of experiments, I studied the activation of various protein kinase C isoforms in response to ischemic stress. Ischemic stress resulted only in the activation of the epsilon isoform in a manner distinct from its activation in response to pharmacologic agents, particularly phorbol ester. In my second series of experiments, I sought to understand the relationship of protein kinase C and the mitogen antigen peptide kinases (MAPK’s). The sustained activation of MAPK’s, particularly ERK 1/2, has been found in other model systems to be important in regulating cell survival. I demonstrated that ERK 1/2 is activated in response to ischemic stress in intestinal epithelial cells, but PKC inhibition did not appear to affect this pathway. Another critical protein in signaling in ischemia, the epidermal growth factor receptor (EGFR), appears to have an important role in regulating ERK 1/2 activation during ischemic stress. This regulation appears to be largely independent of ligand binding to the EGFR itself. The final series of experiments investigated the role of extracellular adenosine on ERK 1/2 activation. Extracellular adenosine does not appear to enhance ERK 1/2 phosphorylation, but it absence prevents full activation. This regulation of ERK 1/2 activation does not appear to be through an adenosine receptor dependent route.
I sought to delineate several signaling pathways important in ischemic stress in intestinal epithelial cells. The epsilon isoform of protein kinase C is activated in a manner distinct from its activation by pharmacologic agents. ERK 1/2, an important protein in signaling during ischemic stress, is not activated by PKC, but rather mostly through a non-EGFR ligand dependent EGFR pathway. Finally, adenosine appears to be important in ERK 1/2, but its mechanism of regulation appears to be adenosine receptor independent.
|School:||University of Cincinnati|
|School Location:||United States -- Ohio|
|Source:||DAI-B 70/08, Dissertation Abstracts International|
|Keywords:||Adenosine, Ischemia/reperfusion injury, MAPK, Protein kinase C|
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