Proteinase 3 activity as a biomarker for disease severity in Chronic Obstructive Pulmonary Disease

COPD is a major unmet health problem worldwide, effecting 10% of adults with no disease modifying treatments. Although largely caused by smoking, most smokers do not develop the disease and, due to the slowly progressive nature of the illness, extensive lung damage occurs before health and routine lung function tests deteriorate leading to a late diagnosis. Understanding the inflammatory processes that drive disease will enable earlier identification of those at risk and is a necessary precursor to targeted management and specific lung therapeutic development.

Inflammation plays a central role in COPD, and key neutrophil enzymes (neutrophil elastase and proteinase 3) remain to date the only proven mediators of the destructive processes causing COPD. These proteinases are especially implicated in the development of emphysema, where destruction of the integrity of the lung alveoli impairs oxygen and carbon dioxide exchange.

Our group has longstanding expertise in COPD, inflammation and in particular neutrophil biology. We run one of the largest COPD cohorts in the UK and have recently been awarded funding to study early COPD by recruiting symptomatic smokers to screen for disease. We run the UK Alpha 1 Anti-trypsin Deficiency (AATD) registry. AATD is rare but the only robustly proven genetic cause of COPD. We also have specific expertise in developing and validating new assays that are central to COPD but also have relevance in other neutrophil based inflammatory conditions.

Work from our department has noted that the neutrophils from patients with COPD behave in a disease specific manner being dysfunctional in their movement and more destructive in their behaviour (features that are not present in other forms of lung inflammation such as bronchiectasis and chronic severe asthma). Coupled with this we know that neutrophils in COPD accumulate in areas where the emphysema occurs and a biological footprint of NE activity is increased in patients with COPD.

More recently we have shown that Proteinase-3 (PR3) may be even more important than Neutrophil Elastase (NE) in these processes and we have developed a new footprint assay for this enzyme. However, the dynamics of PR3 release, the ability to use this marker as a biomarker and its response to treatments are unknown.

The PhD thesis would utilise samples from our extensive patient cohorts and assess the role of PR3 in the development of early COPD and as a driver of disease progression in established COPD. You will validate the new PR3 assay and assess the relationship between PR3 and disease phenotype and severity in COPD and AATD using samples from patients with COPD, AATD and healthy controls. You will develop this assay so that is can be used as a potential biomarker in blood in the stable state, during flares of lung symptoms (termed “exacerbations”) and following treatment with new therapeutics. You will develop tissue models to allow assessment of PR3 and NE inhibitors under development, including a 3D co-culture models of the airways.

This studentship will be supported by the cutting edge clinical and laboratory research facilities within the Centre of Translational Inflammation Research (CTIR), Queen Elizabeth Hospital in a bespoke clinical research centre, providing a visible research presence in the heart of one of the largest hospitals in Europe.

The Clinical Research Facility comprises three day-case beds, six outpatient rooms, 2 specialist rooms, a minor operations room, dental chair and specialist equipment.

The Respiratory laboratory has bench space for 20 researchers, 3 x ESCO cabinets, a fume cupboard, a water purifier and fridge as well as bench centrifuges, pipettes storage areas, western blotting, rtPCR equipment, plate washers and readers and a cell culture incubator as well as a centrifuge room, microscope room, an Astris cell sorter, a BD LSR Fortessa Flow Cytometry Analyzer equipped with HTS (High Throughput Sampler) and designated, alarmed and 24 hour monitored -80OC freezer rooms.

Applicants should have a strong background in inflammation and immunology and ideally a background in innate immunity. They should have a commitment to research in inflammation and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

To apply, please email [Email Address Removed]
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.