Abstract

The overall goal of this project is to study the biochemical factors that regulate anticancer therapy-induced pulmonary injury. Bleomycin hydrolase is a poorly characterized aminopeptidase B- like enzyme that is a major biochemical determinant in bleomycin-induced pulmonary fibrosis. The pulmonary endothelium appears to maintain high levels of this enzyme activity in some species and this may have an important functional role in preventing lung injury.
The specific aims of the proposed research are to: (a) purify and characterize bleomycin hydrolase and other arginine N-terminal exopeptidases, (b) develop monoclonal antibodies directed toward bleomycin hydrolase, (c) study the extent of antigenic homology among the known aminopeptidase B enzymes, (d) measure the content of bleomycin hydrolase in pulmonary and other tissues of various animal species and strains, and (e) determine the relationship between tissue content and activity of bleomycin hydrolase in these animal models to their susceptibility to bleomycin-induced fibrosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043917-06
Application #
3186401
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-09-01
Project End
1992-02-29
Budget Start
1991-03-13
Budget End
1992-02-29
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Lefterov, I M; Koldamova, R P; Lefterova, M I et al. (2001) Cysteine 73 in bleomycin hydrolase is critical for amyloid precursor protein processing. Biochem Biophys Res Commun 283:994-9
Koldamova, R P; Lefterov, I M; Lefterova, M I et al. (2001) Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry 40:3553-60
Fabisiak, J P; Tyurin, V A; Tyurina, Y Y et al. (2000) Nitric oxide dissociates lipid oxidation from apoptosis and phosphatidylserine externalization during oxidative stress. Biochemistry 39:127-38
Woo, E S; Dellapiazza, D; Wang, A S et al. (2000) Energy-dependent nuclear binding dictates metallothionein localization. J Cell Physiol 182:69-76
Lefterov, I M; Koldamova, R P; Lazo, J S (2000) Human bleomycin hydrolase regulates the secretion of amyloid precursor protein. FASEB J 14:1837-47
Pestell, K E; Ducruet, A P; Wipf, P et al. (2000) Small molecule inhibitors of dual specificity protein phosphatases. Oncogene 19:6607-12
Fabisiak, J P; Pearce, L L; Borisenko, G G et al. (1999) Bifunctional anti/prooxidant potential of metallothionenin: redox signaling of copper binding and release. Antioxid Redox Signal 1:349-64
Schwartz, D R; Homanics, G E; Hoyt, D G et al. (1999) The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. Proc Natl Acad Sci U S A 96:4680-5
Koldamova, R P; Lefterov, I M; DiSabella, M T et al. (1999) Human bleomycin hydrolase binds ribosomal proteins. Biochemistry 38:7111-7
Koldamova, R P; Lefterov, I M; Gadjeva, V G et al. (1998) Essential binding and functional domains of human bleomycin hydrolase. Biochemistry 37:2282-90

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