Oral Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Real time assessment of altered signalling pathways in the pathobiology of Chronic Obstructive Pulmonary Disease (#24)

David Skerrett-Byrne 1 2 , Bernadette Jones 1 2 , Rodney J Scott 1 3 , Matthew D Dun 1 4 , Phil M Hansbro 1 2
  1. University of Newcastle, New Lambton Heights, NSW, Australia
  2. VIVA Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  3. Information Based Medicine Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  4. Cancer Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia

Chronic obstructive pulmonary disease (COPD) is the 3rd most common cause of death worldwide, with 50% of patients succumbing to the disease within 10 years of diagnosis. Currently, there is no cure for COPD, only ineffective remedies that reduce its symptoms. Our laboratory has developed a unique and clinically relevant mouse model of cigarette smoke-induced COPD that recapitulates the hallmark features of the human disease in 8 weeks. This is a powerful medical research tool that models the chronic airway, parenchymal inflammation, airway remodelling and emphysema-like alveolar enlargement associated with impaired lung function. To determine the systemic changes responsible for COPD we performed a large-scale comparative and quantitative phosphoproteomic study. This facilitated the assessment of the signalling pathways regulated by chronic exposure to cigarette smoke.  Mice were exposed to our smoking regimen for 4, 6, 8 and 12 weeks and compared to age matched controls (room air). We have assayed changes in the activity of signalling proteins that induce COPD in the lungs of these mice by employing a multidimensional phosphopeptide enrichment strategy coupled to high-resolution quantitative proteomics using isobaric tags. We have progressively tracked 2,000 phosphorylated proteins over the course of the exposure and quantified over 15,000 phosphopeptides. Important structural proteins pathways associated with the airway remodelling associated with COPD were highly overrepresented in our data set. Changes in the phosphoregulation of the actin cytoskeleton, tissue developmental processes and cellular survival were observed. The phosphorylation of IP3R 1, AKAP-1, AGER was only seen only in the lungs exposed to smoke which may be implicated in the pathobiology of COPD. These analyses are providing us with the capacity to progressively track changes associated with chronic exposure to cigarette smoke and will help improve understanding of COPD. Future directions will see the validation of these candidate drug targets in human tissues.