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Noninvasive biomarkers of proteolytic activity in CF


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Collapse Overview 
Collapse abstract
In children with cystic fibrosis (CF) proteolytic activity causes bronchiectasis, resulting in progressive lung disease and marked shortening of life expectancy. One of the long-term objectives for this proposal is to define proteolytic biomarkers that are predictive of future clinical course and disease progression in children with CF. By identifying those children with excessive and more aggressive proteolytic activity, it may be possible to intervene with anti-proteolytic treatments before irreversible airway damage occurs. The main hypothesis is that CF children with more pronounced proteolytic activity, as measured in induced sputum, would have a greater degree of structural and functional lung damage. This hypothesis will be tested through the following specific aims: 1) to determine changes in proteolytic activity by quantitating levels of neutrophil derived proteases (elastase, matrix metalloproteinase Types 2 and 9), lung antiproteases (alpha1antiprotease, secretory leukoprotease inhibitor, tissue inhibitors of metalloproteinase), and elastin breakdown products (desmosine, isodesmosine) in clinical specimens (induced sputum, urine) from CF children, during times of clinical stability, annually over three years; and 2) to correlate these changes in proteolytic activity with structural airway damage (assessed by severity and extent of bronchiectasis on annual high resolution computed tomography scans), functional airway impairment (as determined by annual pulmonary function testing), lower airway bacterial colonization status and bacterial burden, and related morbidities (rates of hospitalization, pulmonary exacerbations). These results will be crucial to evaluating emerging antiproteolytic treatments in children with CF.

Another objective of this application is to enhance and strengthen Dr. Sagel's approach to clinical investigation and patient-oriented research. Dr. Sagel will receive more formal training and education by completing his Ph.D. degree in the UC's Clinical Science Program. He will take courses in clinical epidemiology, bioethics, clinical trial design, pharmacokinetics, and human genetics, and complete a thesis about proteolytic activity in CF. In addition, he will actively participate and train in the Pediatric GCRC, and frequently interact with his sponsor, mentors, and collaborators.
Collapse sponsor award id
K23RR018611

Collapse Time 
Collapse start date
2003-08-01
Collapse end date
2009-07-31

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