Abstract

and specific aims): The goal of this project is to determine the role of granule-associated neutral serine proteinases of polymorphonuclear leukocytes in lung health and disease, focusing, in particular, on the involvement proteinase 3 (PR-3) and leukocyte elastase (LE) in the pathogenesis of emphysema. The proposed studies are based on the following hypotheses: 1) PR-3 and LE are regulated by novel transcription factors, including one that binds to a CG-rich element, that account for their exquisite tissue-and developmental-specific expression; 2) Dipeptidyl peptidase-I (DPP-I), a cysteine proteinase, coordinates the activation of PR-3 and LE, and offers a control point for their expression; and 3) PR-3 and LE are critically important in the pathogenesis of emphysema not only due to their ability to degrade extracellular matrix, but also for because of their attack on intracellular components leading to cell death.
The specific aims are to 1) determine the regulatory elements and factors that dictate PR-3 and LE gene expression; 2) characterize the dipeptidase responsible for activating PR-3 and LE; and 3) determine the role of PR-3 and LE in the development and progression of emphysema.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037615-13
Application #
6030557
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1988-03-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Sturrock, Anne; Franklin, Kerry F; Norman, Kimberly et al. (2004) Human leukocyte elastase gene expression is regulated by PU.1 in conjunction with closely associated cytidine-rich and Myb binding sites. Biochim Biophys Acta 1676:104-11
Jacquinet, E; Rao, N V; Rao, G V et al. (2001) Cloning and characterization of the cDNA and gene for human epitheliasin. Eur J Biochem 268:2687-99
Jacquinet, E; Rao, N V; Rao, G V et al. (2000) Cloning, genomic organization, chromosomal assignment and expression of a novel mosaic serine proteinase: epitheliasin. FEBS Lett 468:93-100
Sturrock, A; Franklin, K F; Wu, S et al. (1998) Characterization and localization of the genes for mouse proteinase-3 (Prtn3) and neutrophil elastase (Ela2). Cytogenet Cell Genet 83:104-8
Rao, N V; Rao, G V; Hoidal, J R (1997) Human dipeptidyl-peptidase I. Gene characterization, localization, and expression. J Biol Chem 272:10260-5
Rao, N V; Rao, G V; Marshall, B C et al. (1996) Biosynthesis and processing of proteinase 3 in U937 cells. Processing pathways are distinct from those of cathepsin G. J Biol Chem 271:2972-8
Sturrock, A; Franklin, K F; Hoidal, J R (1996) Human proteinase-3 expression is regulated by PU.1 in conjunction with a cytidine-rich element. J Biol Chem 271:32392-402
Cannon, G W; Openshaw, S J; Hibbs Jr, J B et al. (1996) Nitric oxide production during adjuvant-induced and collagen-induced arthritis. Arthritis Rheum 39:1677-84
Groutas, W C; Chong, L S; Venkataraman, R et al. (1995) The Gabriel-Colman rearrangement in biological systems: design, synthesis and biological evaluation of phthalimide and saccharin derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3. Bioorg Med Chem 3:187-93
Sugimori, T; Cooley, J; Hoidal, J R et al. (1995) Inhibitory properties of recombinant human monocyte/neutrophil elastase inhibitor. Am J Respir Cell Mol Biol 13:314-22

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