Dr. Mark Murphy

Targeting AATD by Linking Cellular Stress, Senescence and Accelerated Ageing

BACKGROUND

Retention of disease-causing AAT variants in the endoplasmic reticulum (ER) results in cellular stress, not only in the liver but also in immune cells and other tissues. ER stress can cause cellular senescence that in turn causes pro-inflammatory secretion and cellular dysfunction. Hence, the retention of AAT variants may promote senescence in airway and immune cells. Onset of respiratory symptoms in AATD occurs ~10 years before AAT-sufficient COPD counterparts, suggesting accelerated disease processes in AATD. We propose that cellular ageing is enhanced in AATD, coinciding with ER stress, both of which may elicit senescence, and this manifests as immune dysfunction and earlier symptomatic disease.

AIMS

• This study will comprehensively characterise Z-AAT polymer retention, hallmarks of ageing, senescence and inflammation in airway cells and leukocytes in people with AATD-COPD, AAT-replete COPD and healthy counterparts using state-of-the-art spectral flow cytometry, microscopy and multiplex ELISA.
• This study will also investigate the utility of promising senolytic therapies to mitigate the impact of these pathways on immune dysfunction and inflammation in AATD. Airway leukocytes and cultured primary epithelial cells will be targeted ex vivo with (a) an investigational new drug that targets Z-AAT accumulation and/or (b) the senolytic combination dasatinib and quercitin.

This work will be carried out under the mentorship of Prof. Gerry McElvaney, Royal College of Surgeons in Ireland, Beaumont Hospital Dublin.

CURRICULUM VITAE DR. MARK MURPHY

Dr. Murphy obtained a BSc in biochemistry from Trinity College Dublin. He then completed a PhD studying the role of biofilm formation to evasion of neutrophils by pathogens notable in cystic fibrosis, at the Institute of Technology Tallaght, Dublin, Ireland. This was followed by a two-year postdoctoral position conducting further studies of bacterial evasion of host innate immunity with Teagasc, the national agriculture and food research authority of Ireland. He then joined the lab of Prof. Gerry McElvaney at the Royal College of Surgeons in Ireland where he began a research focus on AATD pulmonary innate immune dysfunction, particularly the ways in which this is uniquely pronounced with respect to AAT-replete COPD and the specific mechanisms that drive this.