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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
2M01RR000069-44
Application #
7374362
Study Section
Special Emphasis Panel (ZRR1-CR-9 (01))
Project Start
2006-04-24
Project End
2007-02-28
Budget Start
2006-04-24
Budget End
2007-02-28
Support Year
44
Fiscal Year
2006
Total Cost
$23,223
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Young, Kendra A; Maturu, Amita; Lorenzo, Carlos et al. (2018) The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance, ?-cell function, and diabetes in Hispanics and African Americans. J Diabetes Complications :
Kelsey, Megan M; Braffett, Barbara H; Geffner, Mitchell E et al. (2018) Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. J Clin Endocrinol Metab 103:2309-2318
Kleinberger, Jeffrey W; Copeland, Kenneth C; Gandica, Rachelle G et al. (2018) Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med 20:583-590
Berkowitz, Robert I; Marcus, Marsha D; Anderson, Barbara J et al. (2018) Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial. Pediatr Diabetes 19:191-198
Arslanian, Silva; El Ghormli, Laure; Kim, Joon Young et al. (2018) The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in ?-Cell Function in TODAY. Diabetes Care :
Kriska, Andrea; El Ghormli, Laure; Copeland, Kenneth C et al. (2018) Impact of lifestyle behavior change on glycemic control in youth with type 2 diabetes. Pediatr Diabetes 19:36-44
Venditti, E M; Tan, K; Chang, N et al. (2018) Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes. Diabetes Res Clin Pract 139:24-31
Gidding, Samuel S; Bacha, Fida; Bjornstad, Petter et al. (2018) Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. J Pediatr 192:86-92.e5
Jacobson, Denise L; Lindsey, Jane C; Coull, Brent A et al. (2018) The Association of Fat and Lean Tissue With Whole Body and Spine Bone Mineral Density Is Modified by HIV Status and Sex in Children and Youth. Pediatr Infect Dis J 37:71-77
Levenson, Amy E; Wadwa, R Paul; Shah, Amy S et al. (2017) PCSK9 Is Increased in Youth With Type 1 Diabetes. Diabetes Care 40:e85-e87

Showing the most recent 10 out of 837 publications