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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002822-04
Application #
6634754
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2000-09-15
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$121,341
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Vega, Kenneth J; May, Randal; Sureban, Sripathi M et al. (2012) Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett's esophagus and esophageal adenocarcinoma. J Gastroenterol Hepatol 27:773-80
Sureban, Sripathi M; May, Randal; Lightfoot, Stan A et al. (2011) DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer Res 71:2328-38
Sureban, Sripathi M; May, Randal; Mondalek, Fadee G et al. (2011) Nanoparticle-based delivery of siDCAMKL-1 increases microRNA-144 and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism. J Nanobiotechnology 9:40
May, Randal; Sureban, Sripathi M; Lightfoot, Stan A et al. (2010) Identification of a novel putative pancreatic stem/progenitor cell marker DCAMKL-1 in normal mouse pancreas. Am J Physiol Gastrointest Liver Physiol 299:G303-10
George, Robert J; Sturmoski, Mark A; May, Randal et al. (2009) Loss of p21Waf1/Cip1/Sdi1 enhances intestinal stem cell survival following radiation injury. Am J Physiol Gastrointest Liver Physiol 296:G245-54
Sureban, Sripathi M; May, Randal; Ramalingam, Satish et al. (2009) Selective blockade of DCAMKL-1 results in tumor growth arrest by a Let-7a MicroRNA-dependent mechanism. Gastroenterology 137:649-59, 659.e1-2
May, Randal; Sureban, Sripathi M; Hoang, Nguyet et al. (2009) Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively. Stem Cells 27:2571-9
Sureban, Sripathi M; May, Randal; George, Robert J et al. (2008) Knockdown of RNA binding protein musashi-1 leads to tumor regression in vivo. Gastroenterology 134:1448-58
May, Randal; Riehl, Terrence E; Hunt, Clayton et al. (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26:630-7
George, Robert J; Sturmoski, Mark A; Anant, Shrikant et al. (2007) EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway. Prostaglandins Other Lipid Mediat 83:112-20

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