Chronic pulmonary infection significantly limits the span and quality of life of children and young adults with cystic fibrosis (CF). CF is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and individuals with CF have innate immune alterations, which in turn lead to chronic pulmonary infection, inflammation and, ultimately, airway destruction. The respiratory tracts of most patients with CF (>80% by age 15) are infected with the opportunistic gram-negative bacterium Pseudomonas aeruginosa, and such infection is clearly associated with poor outcome. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial component of CF. P. aeruginosa infection in CF involves colonization early in life. Over many years the bacteria adapt to the CF airway environment with an increased ability to replicate and stimulate inflammatory responses that are ineffective against the bacteria but damage airways. This grant proposes to define common characteristics of P. aeruginosa adaptation to the CF airway by analyzing bacteria isolated from the airways of children with CF as part of a natural history study. Common characteristics of bacteria airway adaptation will be defined using biochemical and phenotypic characterization as well as the most modern techniques in biological research including: DNA microarray analysis, genome sequencing, and quantitative proteomic analysis with mass spectrometry. This proposal will establish prevalence and clinical correlations for the characteristics associated with adaptation to the CF airway by performing cross-sectional and longitudinal studies on CF children with disease of varying severity. The data obtained will test the hypothesis: that characteristics of P. aeruginosa clinical isolates from children with CF can function as markers to predict clinical outcome and therapeutic response. Furthermore, the knowledge obtained from this proposal may direct the development of new therapeutic interventions for CF patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064954-03
Application #
7079272
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Mckeon, Catherine T
Project Start
2004-07-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$717,959
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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D'Argenio, David A; Wu, Manhong; Hoffman, Lucas R et al. (2007) Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients. Mol Microbiol 64:512-33
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Wu, Manhong; Guina, Tina; Brittnacher, Mitchell et al. (2005) The Pseudomonas aeruginosa proteome during anaerobic growth. J Bacteriol 187:8185-90