The stress of major surgical procedures and nutritional deprivation lead to atrophic changes in gut epithelium which significantly affect the outcome of surgical patients. In contrast, hyperplastic growth of intestinal epithelium results in colorectal neoplasm. Cyclooxygenase (COX) enzymes catalyze a key step in the conversion of arachidonic acid to prostaglandins (PGs) which play important roles in modulation of cell proliferation and cell death. Nonsteroidal antiinflammatory drugs (NSAIDs), inhibitors of COX enzymes, suppress growth of transformed intestinal epithelial cells, whereas PGs stimulate intestinal epithelial cell proliferation. The mechanism by which PGs promote intestinal epithelial growth and transformation is poorly understood. Our preliminary studies show that PGE2 induces expression of amphiregulin, an EGF family member, and transactivates receptor tyrosine kinase (RTK)-dependent signaling pathways, including the Ras and the phosphatidylinositol 3-kinase (PI3K) pathways which are essential for intestinal epithelial cell proliferation and transformation.
Specific Aim 1 of this application will use an improved 3-dimensional cell growth model to elucidate the mechanisms by which PGE2 and celecoxib regulate intestinal epithelial cell growth. Functional roles of PGE2 and celecoxib in surgical animal models, including fasting/refeeding and small bowel resection, will be assessed. These experiments will delineate the basic mechanism by which PGs regulate intestinal epithelial proliferation.
Specific Aim 2 will study the signaling mechanisms governing PGE2 trophic action in intestinal epithelial cells. Our focus will be the induction of EGF receptor ligands and transactivation of the PI3K signaling pathway by COX-2/PGE2.
In Specific Aim 3, we will investigate the involvement of COX-2/PGs in Ras-mediated transformation of intestinal epithelial cells. Novel in vitro and in vivo models will be employed to address this question. The long-term goal of this proposal is to provide a complete assessment of molecular mechanisms mediating the trophic action of PGs and the chemopreventive effect of NSAIDs on intestinal epithelial transformation. Our results will provide a novel molecular basis for the development of more effective therapeutic strategies in the regulation of intestinal epithelial growth and transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065615-06
Application #
7336298
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Hamilton, Frank A
Project Start
2004-01-15
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2009-12-31
Support Year
6
Fiscal Year
2008
Total Cost
$309,708
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shao, Jinyi; Sheng, Hongmiao (2010) Amphiregulin promotes intestinal epithelial regeneration: roles of intestinal subepithelial myofibroblasts. Endocrinology 151:3728-37
Shao, Jinyi; Yang, Vincent W; Sheng, Hongmiao (2008) Prostaglandin E2 and Kruppel-like transcription factors synergistically induce the expression of decay-accelerating factor in intestinal epithelial cells. Immunology 125:397-407
Shao, Jinyi; Washington, M Kay; Saxena, Romil et al. (2007) Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin. Carcinogenesis 28:2476-83
Shao, Jinyi; Sheng, Hongmiao (2007) Prostaglandin E2 induces the expression of IL-1alpha in colon cancer cells. J Immunol 178:4097-103
Eklund, Erik A; Sun, Liangwu; Yang, Samuel P et al. (2006) Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation. Biochem Biophys Res Commun 339:755-60
Shao, Jinyi; Sheng, George G; Mifflin, Randy C et al. (2006) Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res 66:846-55
Eklund, Erik A; Newell, John W; Sun, Liangwu et al. (2005) Molecular and clinical description of the first US patients with congenital disorder of glycosylation Ig. Mol Genet Metab 84:25-31
Sun, Liangwu; Eklund, Erik A; Chung, Wendy K et al. (2005) Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 90:4371-5
Shao, Jinyi; Jung, Chaeyong; Liu, Chunming et al. (2005) Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. J Biol Chem 280:26565-72
Shao, Jinyi; Evers, B Mark; Sheng, Hongmiao (2004) Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells. J Biol Chem 279:14287-93