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Understanding mechanisms of lung destruction in patients with non-tuberculous mycobacterial pulmonary infection

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  • Full or part time
    Prof C O'Kane
    Dr G Schroeder
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Mycobacterium avium (M avium) is the commonest form of non-tuberculous mycobacterial (NTM) infection, and is prevalence is rising exponentially in the developed world. NTM lung pulmonary disease is characterised by bronchiectasis and/or cavitation, indicating destruction of the pulmonary parenchyma during infection. Even with successful treatment an ongoing decline in lung function occurs. Anti-mycobacterial strategies are poor, taking a minimum of 18 months with triple antibiotic therapy, and do not prevent decline in pulmonary function.

Extracellular matrix proteins act as the scaffold for lung epithelial and stromal cells. Type I collagen is the main structural supporting collagen of the lung, and elastin provides the major elastic recoil. Degradation of both is required to drive cavitation and bronchiectasis. In tuberculosis (TB) there is compelling evidence that host derived proteases cause degradation of collagen and elastin fibres. Matrix metalloproteinase (MMP)-1, a collagenase, and MMP-7, an elastase, are induced during TB and the increase correlates with the extent of radiological change.

Mechanisms driving tissue destruction in M avium infection are less well understood. We have shown in healthy monocyte derived macrophages (MDMs) that M avium has a specific MMP signature, characterised by unopposed MMP-1/-7 secretion, which are regulated by ERK and PI3kinase dependent pathways. In this study we wish to characterise the MMP activity and profile of sputum from patients with MAC infection, compared with patients with underlying chronic lung disease but no NTM infection, and healthy age matched controls. We will investigate mechanisms regulating MMP secretion in patients with M avium infection. These data will allow us to test - in isolated cells, sputum and in an ex vivo human lung model of M avium infection - the capacity of potential inhibitors to reduce MMP activity in the presence of M avium, and decide whether to proceed to further testing of such inhibitors in clinical trials, as an adjunct to NTM anti-microbial therapy.

ENTRY REQUIREMENTS

We are looking for graduates who are enthusiastic and strongly motivated to use the most innovative approaches to address key global challenges in infectious diseases, antimicrobial resistance, animal health, climate change and sustainability. Applicants should have a degree in biological sciences or a related discipline.

The minimum academic requirement is an Upper Second Class Honours degree from a UK or ROI HE provider (or qualifications deemed equivalent by the University).

Students wishing to apply to Queen’s University Belfast (and for whom English is not their first language) must be able to demonstrate their proficiency in English in order to benefit fully from their course of study or research. For more information on English Language requirements see www.qub.ac.uk/EnglishLanguageReqs

Funding Notes

The studentship will be funded by the Department for the Economy (DfE). Please read the full information on eligibility criteria: https://www.economy-ni.gov.uk/publications/student-finance-postgraduate-studentships-terms-and-conditions

However, there may be flexibility to fund a small number of exceptional International applicants.

General enquiries about the programme may be directed to [Email Address Removed]

References

Please visit the School of Medicine, Dentistry and Biomedical Sciences, Centre for Experimental Medicine, website for further details about the Centre:

http://www.qub.ac.uk/research-centres/CEM/

When applying, please choose 'MEDICINE' as your subject area/School.

Related Subjects



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