application) Prostaglandins (PGs) specifically PGE2 has been shown to regulate intestinal stem cell survival and crypt epithelial apoptosis in response to radiation injury. 16,16 dimethyl PGE2 (dmPGE2) a stable PGE2 analog has also been shown to reverse the effects of DSS in epithelial proliferation in cecal crypts. The mechanism by which PGE2 protects intestinal stem cells from radiation injury and colonic transit cells from DSS injury is unclear. PGE-2 is the most important PG involved in the maintenance of gastrointestinal integrity and is thought to be responsible for protecting the gut epithelium from environmentally induced damage. Radiation injury in adult mice results in increased expression of Cox-1 and elevated PGE2 levels 3-5 days after irradiation, the time when crypt regeneration occurs. PGE2 mediates its biologic effects through binding to membrane bound G-protein coupled receptors, termed EP receptors. The EP receptors are encoded by four separate genes (EPI, EP2, EP3, and EP4 ). The distribution of these receptors in the normal gastrointestinal tract is beginning to be explored and the role of these receptors in the regulation of the gastrointestinal response to injury is currently unknown. We have recently developed [sic] demonstrating that EP2 and EP4 mRNA are induced by radiation injury in mouse gastrointestinal epithelial cells. EP2 and EP4 protein are similarly induced by radiation injury in the intestinal epithelial cell line I407. These results suggest that EP receptor expression in the gastrointestinal tract can be modulated by acute injury. Similarly, we have also shown that Cox-2 is induced in I407 cells via a p38 dependent mechanism. The central hypothesis of this proposal is that 1). EP2 and EN receptors are induced in gastrointestinal epithelial cells through a p38 dependent mechanism and 2. The protective functions of PGE2 on epithelial cells in intestinal injury is mediated through EP2 and EP4. We propose to use the radiation injury and DSS colitis models to test this hypothesis through the following Specific Aims: 1. To define the regional and cell specific distribution of EP receptors in normal and injured adult mouse intestine and colon 2. To define the mechanism of the induction of EP2 and EP4 by irradiation in the human intestinal epithelial cell line I407. and 3. To determine the mechanism by which EP receptor isoforms mediate the effects of prostaglandins on intestinal stem cell survival, crypt epithelial apoptosis and crypt epithelial proliferation following injury. We believe that a better understanding of the role of PGE2 receptors in the regulation of stem cell survival, apoptosis and epithelial proliferation will be of great importance in the understanding of the pathogenesis of gastrointestinal malignancy and gastrointestinal inflammatory diseases.
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