NONINVASIVE BIOMARKERS OF PROTEOLYTIC ACTIVITY IN CHILDREN WITH CYSTIC FIBROSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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, will 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 metalloproteinases types 2 and 9), lung antiproteases (alpha1-antiprotease, secretory leukoprotease inhibitor, tissue inhibitors of metalloproteinases), and elastin breakdown products (desmosine, isodesmosine) in clinical specimens (induced sputum, urine) from CF children, during times of clinical stability, annually over 3 years; 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 as well as biochemically through measurement of elastin breakdown products in sputum and urine), 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); and 3) to examine the influence of genetic modifiers on airway proteolytic activity by determining if protease levels are associated with polymorphisms in genes that are believed to modify CF lung disease (MBL, TNF , TGF- , and A1AT). These results will be crucial to evaluating emerging anti-proteolytic treatments in children with CF. Another objective of this clinical research protocol 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. in the University of Colorado'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.