Proper function of the epithelial lining the gastrointestinal (GI) tract depends upon tight regulation of a number of cellular and biochemical events that organize complex signal transduction pathways. An important question regarding the continuous and rapid renewal of this tissue, normally and following injury is how decisions about cell proliferation, migration and death are made and how aberrant processing of these decisions results in disease from ulceration to tumorigenesis. Tumor necrosis factor (TNF) receptor (R) family members are important in regulation of growth, migration, differentiation and apoptosis of a number of cells and tissues. Studies from our laboratory and others indicate these proteins play key regulatory roles in intestinal development and homeostasis. Their expression, activation or signal transduction pathways are altered in a number of gastrointestinal disorders including inflammatory bowel diseases, celiac disease, Helicobacter pylori gastritis, necrotizing enterocolitis and non-steroidal anti-inflammatory drug-induced gastrointestinal diseases. In the current proposal we will extend our previous findings under the initial funding of this program using state-of-the art molecular, genetic and proteomic approaches in cell culture and mouse models to further test our hypothesis that TNFR family members determine intestinal homeostasis by mediating opposing TNF-induced responses on epithelial cell proliferation, migration, differentiation and apoptosis. Therefore, our Specific Aims are to: 1. determine the signal transduction pathways initiated by TNFR1 regulating intestinal cell growth inhibition, survival and migration, 2. identify and characterize downstream targets of TNFR2 activation that promote epithelial cell growth and migration and 3. determine the role of TNFRs in regulating in vivo intestinal epithelial response to TNF, injury and repair. The proposed studies will significantly enhance our understanding of the roles and mechanisms of action for TNFRs effects on intestinal epithelial health with implications for a number of human gastrointestinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056008-10
Application #
7477899
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Carrington, Jill L
Project Start
1999-08-15
Project End
2009-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
10
Fiscal Year
2008
Total Cost
$308,686
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Dubé, Philip E; Liu, Cambrian Y; Girish, Nandini et al. (2018) Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 8:9119
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Miguel, Jennifer C; Maxwell, Adrienne A; Hsieh, Jonathan J et al. (2017) Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci 130:90-96
Yan, F; Liu, L; Cao, H et al. (2017) Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood. Mucosal Immunol 10:117-127
Wang, Y; Liu, L; Moore, D J et al. (2017) An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells. Mucosal Immunol 10:373-384
Zhao, Gang; Liu, Liping; Peek Jr, Richard M et al. (2016) Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. J Biol Chem 291:20462-72
Li, Ran; Zhang, Yufeng; Polk, D Brent et al. (2016) Preserving viability of Lactobacillus rhamnosus GG in vitro and in vivo by a new encapsulation system. J Control Release 230:79-87
Liu, Cambrian Y; Dubé, Philip E; Girish, Nandini et al. (2015) Optical reconstruction of murine colorectal mucosa at cellular resolution. Am J Physiol Gastrointest Liver Physiol 308:G721-35
Dubé, Philip E; Punit, Shivesh; Polk, D Brent (2015) Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 308:G161-70
Punit, Shivesh; Dubé, Philip E; Liu, Cambrian Y et al. (2015) Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis. Gastroenterology 149:993-1005.e2

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