The human intestine is lined by a single layer of protective epithelial cells, which possess properties such as barrier and ion transport functions. In addition, the epithelium functions as a component of the innate immune system, including expression of functional antimicrobial peptides. Recent studies from our laboratory indicate that intestinal epithelial cells express the anti-infective molecule bactericidal permeability-increasing protein (BPI), a peptide with potent antimicrobial and endotoxin-neutralizing activity. Preliminary studies for this application indicate that: a) intestinal epithelial BPI is functionally important in regulating epithelial responses to endotoxin; b) that bacterial-derived products can regulate epithelial expression of BPI; and c) that the murine homolog of BPI is expressed on intestinal epithelia. In the proposed studies we will systematically define activation pathways of epithelial BPI production and define regulatory pathways both in vitro and in vivo. Parallel experiments will be done utilizing epithelial cell lines and native human intestinal tissue to define these principles. First, we will elucidate the basis of epithelial BPI production. Using molecular, morphologic and functional readouts, we will elucidate molecular pathways of epithelial BPI expression. Second, we will define the role of epithelial BPI in murine colitis. Third, we will profile the expression patterns of epithelial BPI protein and mRNA in patients with linflammatory bowel disease (IBD). Successful completion of the Aims outlined in this application will yield insight into the role of endogenous antimicrobial peptides in the pathogenesis of IBD and will provide I predictive value for future development of experimental therapeutics for such disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21DK065768-03
Application #
7342225
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2004-06-01
Project End
2007-05-31
Budget Start
2006-08-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$50,834
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Campbell, Eric L; Serhan, Charles N; Colgan, Sean P (2011) Antimicrobial aspects of inflammatory resolution in the mucosa: a role for proresolving mediators. J Immunol 187:3475-81
Canny, Geraldine; Cario, Elke; Lennartsson, Andreas et al. (2006) Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein. Am J Physiol Gastrointest Liver Physiol 290:G557-67
Canny, Geraldine O; Trifonova, Radiana T; Kindelberger, David W et al. (2006) Expression and function of bactericidal/permeability-increasing protein in human genital tract epithelial cells. J Infect Dis 194:498-502
Canny, Geraldine; Colgan, Sean P (2005) Events at the host-microbial interface of the gastrointestinal tract. I. Adaptation to a microbial world: role of epithelial bactericidal/permeability-increasing protein. Am J Physiol Gastrointest Liver Physiol 288:G593-7