Urease plays a significant role in bacterial infections of both the urinary tract and the gastroduodenal region. At both sites of infection urease enhances the survival of the infecting organism by providing a more suitable environment for growth. The production of urease also increases damage to the infected organs by direct cellular injury from ammonia. In addition, urinary tract infections with a urea-producing bacteria can result in the formation of bladder and kidney stones. Infection of the urinary tract by urease-producing organisms results in a severe inflammatory response. This proposal examines the urease- specific inflammatory response, since it may lead to renal dysfunction and ultimately glandular scarring or destruction. Our results will be compared to the significant inflammation associated with infection by the urease- producing gastroduodenal pathogen Helicobacter pylori. Understanding the mechanisms of the host response to urease-positive organisms will be important in the development of novel strategies to limit mucosal damage associated with these infections. The two most common urease-producing uropathogens, Providencia stuartii and Proteus mirabilis, express urease in response to urea in the growth medium. Urea-dependent expression requires the regulatory protein UreR, which is a member of the AraC-family of transcriptional activators. In these studies, the UreR-urea interaction and the mechanisms of transcription by UreR will be examined. Urea, which is in high concentrations on human urine, is able to freely diffuse into bacteria, and the UreR-urea interaction is an initial signal to the infecting agent that it is in the urinary tract. Since in urinary tract pathogens UreR is acting as both a sensor of the environment and an activator of transcription, studies on the UreR-urea interaction are important for defining the role of this protein in infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
9R01DK050495-06
Application #
2151506
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1990-04-01
Project End
1999-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Turgeon, Judith L; McDonnell, Donald P; Martin, Kathryn A et al. (2004) Hormone therapy: physiological complexity belies therapeutic simplicity. Science 304:1269-73
Sathya, Ganesan; Jansen, Michelle S; Nagel, Susan C et al. (2002) Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins. Endocrinology 143:3071-82
Gendlina, Inessa; Gutman, Delia M; Thomas, Venetta et al. (2002) Urea-dependent signal transduction by the virulence regulator UreR. J Biol Chem 277:37349-58
Giangrande, P H; Kimbrel, E A; Edwards, D P et al. (2000) The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 20:3102-15
Thomas, V J; Collins, C M (1999) Identification of UreR binding sites in the Enterobacteriaceae plasmid-encoded and Proteus mirabilis urease gene operons. Mol Microbiol 31:1417-28
Tetel, M J; Giangrande, P H; Leonhardt, S A et al. (1999) Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol Endocrinol 13:910-24
Beaudenon, S L; Huacani, M R; Wang, G et al. (1999) Rsp5 ubiquitin-protein ligase mediates DNA damage-induced degradation of the large subunit of RNA polymerase II in Saccharomyces cerevisiae. Mol Cell Biol 19:6972-9
Giangrande, P H; Pollio, G; McDonnell, D P (1997) Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem 272:32889-900
D'Orazio, S E; Thomas, V; Collins, C M (1996) Activation of transcription at divergent urea-dependent promoters by the urease gene regulator UreR. Mol Microbiol 21:643-55