The intestinal epithelium is a highly dynamic cell compartment in which rapid proliferation must be closely balanced by the rate of subsequent cellular differentiation and cell loss. Maintenance of this balance must require complex interaction of those factors which control cell proliferation and those which lead to functional maturation. In the studies encompassed by this proposal, the role of previously recognized growth factors (including TGF beta, EGF, PDGF and peptide hormones) on intestinal cell proliferation and differentiation will be defined using organ culture, primary isolated cell culture and established cell lines. Binding of peptide growth factors to epithelial cell populations in proximal and distal small intestinal as well as colonic epithelium will be characterized. The effects of these factors singly and in combination, on thymidine incorporation, glycoprotein structure and enzlymatic and molecular markers of differentation will be determined. A second major thrust of this proposal will be the isolation of additional peptide growth factors which may specifically regulate intestinal proliferation and differentiation. Preliminary studies have identified a peptide in the intestinal villus distinct from known growth factors which specifically inhibits intestinal cell proliferation and may promote commitment to functional differentiation. This factor will be isolated, characterized and its mechanism of action defined using molecular biologic approaches to characterize cellular transcripts following exposure to this factor. A second previously unrecognized growth factor(s) which stimulates cellular proliferation in the intestinal and colonic crypt has been found as a product of human colonic carcinoma cells. This proliferation promoting substance will be purified and its mechanism of action examined. The interaction of these different factors may provide the regulation essential to these complex and dynamic epithelial cell populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041557-03
Application #
3242351
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-09-01
Project End
1992-06-30
Budget Start
1990-09-01
Budget End
1992-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Cario, E; Gerken, G; Podolsky, D K (2007) Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359-74
Hisamatsu, Tadakazu; Suzuki, Manabu; Podolsky, Daniel K (2003) Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells. J Biol Chem 278:32962-8
Beck, Paul L; Rosenberg, Ian M; Xavier, Ramnik J et al. (2003) Transforming growth factor-beta mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells. Am J Pathol 162:597-608
Cario, Elke; Brown, Dennis; McKee, Mary et al. (2002) Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol 160:165-73
Cario, E; Gerken, G; Podolsky, D K (2002) ""For whom the bell tolls!"" -- innate defense mechanisms and survival strategies of the intestinal epithelium against lumenal pathogens. Z Gastroenterol 40:983-90
Goke, M N; Cook, J R; Kunert, K S et al. (2001) Trefoil peptides promote restitution of wounded corneal epithelial cells. Exp Cell Res 264:337-44
Nishiyama, R; Sakaguchi, T; Kinugasa, T et al. (2001) Interleukin-2 receptor beta subunit-dependent and -independent regulation of intestinal epithelial tight junctions. J Biol Chem 276:35571-80
Cario, E; Podolsky, D K (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010-7
Podolsky, D K (2000) Review article: healing after inflammatory injury--coordination of a regulatory peptide network. Aliment Pharmacol Ther 14 Suppl 1:87-93
Cario, E; Rosenberg, I M; Brandwein, S L et al. (2000) Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol 164:966-72

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