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Characterisation of neutrophil reprogramming in chronic lung inflammation


School of Medicine

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Prof J Chalmers No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Chronic inflammatory lung diseases like COPD and bronchiectasis affect millions of people in the UK and worldwide and have a major impact on patients in terms of impaired quality of life, daily symptoms and premature mortality. There is currently no effective treatment for bronchiectasis and a deeper understanding of the disease is therefore vital.

Neutrophil infiltration of the airways is central to the pathogenesis and progression of bronchiectasis, which is characterised by a vicious cycle of infection, inflammation, tissue damage and impaired mucus and pathogen clearance (1). Neutrophils—the most abundant immune cell in the circulation and first-responders to infection—are often called a “double-edge sword.” They are crucial for host defence and clearance of pathogens but also cause damage to host tissues. In our lab we have shown that levels of neutrophil-derived proteins in the airways, such as neutrophil elastase, correlate with disease severity in bronchiectasis (2,3) and that targeting neutrophils provides clinical benefits (4). In the context of chronic inflammation, these cells contribute to the vicious cycle of lung injury, and their propensity for damage is increased whilst their antimicrobial activity is reduced.

In chronic diseases, neutrophils become “reprogrammed” referring to an increased tendency to pro-inflammatory responses and release of damaging mediators. The mechanisms of cellular reprogramming have not been characterised in neutrophils.

In an extensive and well-funded translational study we will perform the most in-depth characterisation of peripheral and lung neutrophils to-date to identify changes in immune cell function and characterise inflammation with the aim to identify novel therapeutic targets.

This project will involve neutrophil isolation from both patient peripheral blood and bronchoalveolar lavage fluid. A number of methods will be employed to study these cells including proteomics, mass cytometry and functional assays in vitro to investigate bacterial phagocytosis and killing, NETosis, migration and activation of pro-inflammatory pathways. Cells from patients with lung disease will be compared to matched controls without lung disease and pathways implicated in neutrophil reprogramming will be identified and therapeutically targeted in vitro.

Full training in the methodologies used will be provided. The student will join the respiratory infection research group at the University of Dundee which includes 3 principle investigators, 4 post-docs, 3 current PhD students, 4 technicians and a bioinformatician. The student will join a highly collegiate and supportive environment dedicated to high quality research training. The clinical research component will be supported by a team of clinical researchers based at the Clinical Research Centre at Ninewells Hospital. The group has a track record of publishing high impact clinical and translational research.

To apply please send a cover letter, curriculum vitae and two references to: [Email Address Removed] by the 18th October 2020.

References
1. Finch S…….Chalmers JD. Pregnancy Zone Protein is Associated with Airway Infection, Neutrophil Extracellular Trap Formation and Disease Severity in Bronchiectasis. Am J Respir Crit Care Med 2019;200(8):992-1001
2. Chalmers JD et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med 2017;195(10):1384-1393.
3. Dicker AJ….. Chalmers JD. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in Chronic Obstructive Pulmonary Disease. J Allergy Clin Immunol. 2018 Jan;141(1):117-127
4. Chalmers JD et al, A phase 2 trial of the DPP1 inhibitor Brensocatib in bronchiectasis. New England Journal of Medicine 2020. In press

Start Date - 30 November 2020

To apply please send a cover letter, curriculum vitae and two references to: [Email Address Removed] by the 18th October 2020.

References
1. Finch S…….Chalmers JD. Pregnancy Zone Protein is Associated with Airway Infection, Neutrophil Extracellular Trap Formation and Disease Severity in Bronchiectasis. Am J Respir Crit Care Med 2019;200(8):992-1001
2. Chalmers JD et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med 2017;195(10):1384-1393.
3. Dicker AJ….. Chalmers JD. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in Chronic Obstructive Pulmonary Disease. J Allergy Clin Immunol. 2018 Jan;141(1):117-127
4. Chalmers JD et al, A phase 2 trial of the DPP1 inhibitor Brensocatib in bronchiectasis. New England Journal of Medicine 2020. In press

Funding Notes

European Respiratory Society. Stipend level to be confirmed with the applicant.

Candidates must have a first or upper second class honours degree or significant research experience.


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