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The Colorado Clinical Proteomics Program focuses on improving the understanding and treatment of pediatric lung diseases, including asthma, bronchopulmonary dysplasia (BPD), cystic fibrosis (CF), and pulmonary arterial hypertension (PAH). Our program aims to develop and validate protein biomarkers that will enhance clinical care. Specific goals include establishing biomarker panels to address frequent exacerbations in asthma, identifying rapid progressors in CF and BPD, and developing educational resources for better patient management. By leveraging non-invasive sampling techniques, we strive to provide insights into disease mechanisms and improve outcomes for affected children.
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Colorado Clinical Proteomics Program 1. Pediatric Lung Disease 2. Hypothesis and Specific Aims 3. Colorado Clinical Proteomics Program - Organization - Setting - Cores - Networks - Special Features Colorado Clinical Proteomics Program
Childhood Adult Lung Disease Morbidity Mortality Lung Disease Protein Biomarkers - Assessment difficult - Non-invasive sampling - Small volume specimens Pediatric Lung Disease Asthma, Bronchopulmonary Dysplasia, Cystic Fibrosis, Pulmonary Artery Hypertension Colorado Clinical Proteomics Program
Asthma Reversible Airway Obstruction Pediatric Asthma - 10-35% of all children - Quality of Life, School Attendance - Morbidity, Hospitalization 4/1000 - Mortality - Cost (Sennhauser et al, 2005; Engelsvold, Omyar, 2003; Myers, 2000) Colorado Clinical Proteomics Program
Bronchopulmonary Dysplasia (BPD) - 0.2% to 1% newborns (10,000-40,000/yr) - 60% Readmission rate - Increasing rate of premature births - Surfactant - Decreased severity - No change in Incidence • BPD • Chronic Lung Disease • Preterm Infants • Mechanical Ventilation • All Lung Components (Wen et al, 2004) Colorado Clinical Proteomics Program
Cystic Fibrosis (CF) - 17,000 Children - 20% Hospitalized - Progressive Loss Of Lung function - Median age of Death (25 years) - Cost • Cystic Fibrosis • Genetic • Failure of • Airway Defense (CF Foundation Patient Registry 2003, Bethesda, MD) Colorado Clinical Proteomics Program
Pulmonary Arterial Hypertension (PAH) • PAH • CHD • Idiopathic • Developmental • Abnormalities • Mortality – 10 year 40% • Morbidity • Prolonged hospitalizations • 240 followed at Colorado (Yung et al, 2004) Colorado Clinical Proteomics Program
Clinical Proteomics Potential • Asthma BPD CF PAH • Population screening Yes • Susceptibility • Staging • Rapid progression study study • Exacerbation • - Identification • - Susceptibility study • Response to tx study study • Toxicity with tx • Clin Trial stratification • Outcome Measures • Clues to Pathogenesis • Inflammation,Fibrosis Yes(?) Yes Yes Yes Colorado Clinical Proteomics Program
Hypothesis and Specific Aims • Hypothesis: Development and Validation of Protein Bio- • Markers will lead to improved care in Pediatric Lung Disease • Aim 1. Establish a Clinical Proteomics Program in Pediatric • Lung Disease comprising five cores to develop and validate • panels of Protein Biomarkers • Aim 2. Address specific issues in Pediatric Lung Disease • through panels of protein biomarkers: • Asthma – frequent exacerbations, failure to respond to Tx • CF, BPD – identification of rapid progressors • PAH – failure to respond to Tx • Aim 3. Develop Educational Program in Clinical Proteomics • Aim 4. Develop a National Resource for NHLBI investig. Colorado Clinical Proteomics Program
Colorado Clinical Proteomics Program – Organization NHLBI Clinical Proteomics Steering Committee Colorado Steering Committee - Heads of Core, M. Duncan, Proteomics Consultant. - Clinical Core – F. Accurso, MD (PI) - Laboratory Core – R. Harbeck, PhD - Data Management/Biostatistics – J. Murphy, PhD - Educational Core – R. Deterding, MD; L. Shroyer, PhD - Administrative Core – F. Accurso, MD Colorado Clinical Proteomics Program
Colorado Clinical Proteomics Program – Setting Childrens Hospital Clinical, Lab, Admin 3 miles National Jewish Center Clinical, Lab, DMU/Biostats 6 blocks University of Colorado Veterans Administration Education, Biostats Colorado Clinical Proteomics Program
Clinical Core Director: F. Accurso, MD Asthma: S. Szefler, MD, National Jewish - CAMP, ICAC BPD: S. Abman, MD; J. Kinsella, MD Children’s Hospital, University - NHLBI funded trial of nitric oxide in prevention of BPD PAH: S. Abman, MD; D. Ivy, MD, Children’s Hospital, Univ. - Local, Multicenter trials CF: F. Accurso, MD, Children’s Hospital, Univ. - CF Foundation Therapeutics Development Network Regulatory Compliance: HIPAA, Institutional Review Board Colorado Clinical Proteomics Program
Specimen Collection Sample Processing Storage Analysis Validation Luminex Platform Laboratory Core Director: R. Harbeck, PhD IL-1-8-10, -12, -13, 15, GM-CSF, IFN, TNF, eotaxin, MCP-1, RANTES, MIP-1, VEG F Colorado Clinical Proteomics Program
Data Management/Biostatistics Core Director: J. Murphy, PhD Phase 1Phase 2Phase 3Phase 4Phase 5 Exploratory Clinical Assay Retrospective Prospective Large Scale Studies Development/ Longitudinal Longitudinal Application Validation Validation Validation • Data Management: • - Implementation • - Regulatory Compliance • Biostatistics: J. Murphy; G. Zerbe, PhD. • - Statistics appropriate for each Phase (Pepe et al, 2001; Srinivas et al, 2002) Colorado Clinical Proteomics Program
Education Core Co-Directors: R. Deterding, ,MD, L. Shroyer, PhD • Clinical Science Program, K30, med school curriculum • Local, National and Web Based Goals • Curriculum Design, Implementation, Evaluation, Dissemination • Trainees: Multidisciplinary backgrounds, all levels Year 1 Year 2 Year 3 Year 4 Curriculum Pilot Local Full Local Evaluate Local Development Start National National (ATS, ACCP) Start Web based Web based Evaluate National Colorado Clinical Proteomics Program
Clinical Study Timeline: CF Colorado Clinical Proteomics Program
Colorado Clinical Proteomics Program 1. Pediatric Lung Disease 2. Hypothesis and Specific Aims 3. Colorado Clinical Proteomics Program - Organization - Setting - Cores - Networks - Special Features Collaboration with M. Duncan, Proteomics, Randox Laboratories, Protein Arrays Colorado Clinical Proteomics Program
Experience with Matrices Other than Plasma or Serum • Sputum (Sagel et al. 2001) • BAL (Khan et al. 1995) • Bronchial Brushing (Wooldridge et al, 2004) • Breath Condensate • Urine • - Proteomic Study of Urinary Biomarkers in CF • Exacerbation • - Collaboration with M. Duncan and S. Hunsucker Colorado Clinical Proteomics Program
Protein Biomarker Timeline:Immunoreactive Trypsinogen (IRT) 1979 1991 1995 2004 Clinical Benefit (Farrell et al) Pilot CF Screening (Eliot et al) Validated (Hammond et al) CDC, CF Found. Endorse- ment Colorado Screening Program (n>1,000,000) We need to do better. Colorado Clinical Proteomics Program