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Symposium 18 Tools for Measuring Early Lung Disease

Symposium 18 Tools for Measuring Early Lung Disease. Proteomic biomarkers of Lower Airway Disease. Frank Accurso, MD Professor of Pediatrics CF Center Director University of Colorado Denver, Colorado, USA. 100. 90. 80. 70. 60. 2001. 50. 40. 30. 6. 18.

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Symposium 18 Tools for Measuring Early Lung Disease

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  1. Symposium 18 Tools for Measuring Early Lung Disease Proteomic biomarkers of Lower Airway Disease Frank Accurso, MD Professor of Pediatrics CF Center Director University of Colorado Denver, Colorado, USA

  2. 100 90 80 70 60 2001 50 40 30 6 18 Lung Disease in CF: Clinical Course (CFF registry, 2001) • Decline in Lung function • Acute Exacerbations • Structural Lung Injury Years

  3. CF Pathophysiology Neutrophils, Macrophages, Bacteria Epithelial Cells Lymphocytes (Hubeau et al, 2001) Macrophages (Durieu et al, 1998)

  4. Proteomic Biomarkers of Lower Airway Disease: Overview • Protein Biomarkers of disease • Proteolytic and Oxidative Injury in the CF airway • Should the lower airway be sampled in clinic? • Take home message • – There is compelling evidence that proteolytic and • oxidative damage occur early in CF indicating • the need for early treatment.

  5. Biomarkers and Proteomics Biomarker A characteristic that is objectively measured and evaluated as an Indicator of normal biologic or pathogenic process or Pharmacological responses to a Therapeutic intervention (www.fda.gov) Proteomics The comprehensive, complete qualitative and quantitative description of proteins in a biological sample.

  6. Protein Biomarkers in CF Need Biomarker(s) 1. Clues to Pathogenesis ? 2. Rapid decline in lung function No 3. Ongoing Lung Structural Injury No 4. Identification of Infection No 5. Exacerbation a. Identification No b. Susceptibility No 6. Response to treatment No 7. Clinical Trials a .Stratification No b. Efficacy ?Elastase, IL-8, LTB4 8. Toxicity with treatment No 9. Staging No 10. Newborn Screening Yes

  7. Protein Biomarkers from Proteomics Proteomic Experiment Mass Spectrometry Potential Protein Biomarkers - Western Blot - ELISA - activity Proteome proteases Proteins identified Elastase Cathepsin MMPs Proteinase K Panels of Protein Biomarkers - Statistical Techniques are improving. - Difficult to apply laboratory validation techniques to panels. cytokines Limitations - protein size - abundance Ollero et al., Proteomics, 2006

  8. Cytokines are plentiful in the CF airway Armstrong et al, 2005

  9. Clustering distances between two observations • Euclidean distances are roots of sums of squares distances (the distance between two observations in n-dimensional space with n variables) • Manhattan distance is not a straight line &larger R. Deterding and S. Heltshe

  10. Single Linkage: Individuals are merged with another individual that has the least distance. That cluster is then merged with the most similar cluster, etc.. Complete Linkage: At each merge, the distance between clusters is determined by the distance between the two elements (one from each cluster) that are most distant. Average Linkage: At each merge, the distance between clusters is determined by the average distance between all pairs of items (where one member of a pair belongs to each cluster) Linkage Methods in clustering 3 1 4 2 5 3 1 4 2 5 3 1 4 2 5 R. Deterding and S. Heltshe

  11. Proteases are greatly increased in the early CF airway Armstrong, 2005

  12. Proteolytic Damage in the CF airway • Complement receptor – M. Berger, 1989 • Surfactant Protein A – Rubio, 2004, Von Bredow, Griese, 2003, • Alpha one antitrypsin – Sloane, 2005 • IgG - Sloane, 2005 • Phosphaphosphatidylserine receptor, CD36, - apoptosis • - Vandivier,2002 Alpha one antitrypsin Sloane, 2005

  13. Oxidative Damage in the CF Airway • Protein carbonyls - Starosta, Griese, 2006 • Lipid Hydroperoxides – Hull, 1997 • Active myeloperoxidase – Kettle, 2004 Chlorinated tyrosines in BAL Kettle, 2004

  14. Antibiotic treatment does not necessarily decrease inflammation in CF Tobi treatment eradicated Pseudomonas but did not change airway inflammation (Gibson, 2003)

  15. Microbial Diversity in an 8 year old with CF (culture negative) Culture neg Treatable 61 patients – 7 cx negative (6 identified) - 4 additional microbes Culture neg Treatable

  16. Future Clinical Evaluation Enter Clinic (Ht, Wt, VS) Pulmonary Function Testing Lab Sputum Induction Lab (Molecular Microbial Dx, Inflammatory biomarkers) Exam Room - Clinical Evaluation - Lung Biomarker Profile - Personalize Treatment - Enrollment in Trial Point of Service Testing

  17. Proteomic Biomarkers of Lower Airway Disease: Overview • Protein Biomarkers of disease • Proteolytic and Oxidative Injury in the CF airway • Should the lower airway be sampled in clinic? • Take home message • – There is compelling evidence that proteolytic and • oxidative damage occur early in CF indicating • the need for early treatment.

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