Selective targeting of furin for the treatment of fibrotic lung disease.


   School of Pharmacy

  Prof Lorraine Martin  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Furin, a proprotein convertase has been established as a therapeutic target across several disease areas to include chronic airways diseases and infectious disease, such as COVID-19 (reviewed in our recent publication, Douglas et al, 2023). In cystic fibrosis (CF) elevated furin levels increases the activity of the epithelial sodium channel (ENaC) leading to airways dehydration and impaired mucociliary clearance (MCC) mechanisms, key features that contribute to disease progression. Other furin substrates include TGF-β, active forms of which are increased in CF as well as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF). In the lungs aberrant TGF-β levels are associated with neutrophilic inflammation, reduced pulmonary function and increased hospitalisation. Long-term exposure to elevated TGF-β increases matrix metalloproteinase (MMP) levels which cause lung tissue remodelling and the build-up of scar tissue (fibrosis). Of note, progression of CF and COPD, but IPF in particular, is associated with significant levels of fibrosis which restricts lung function contributing to early mortality. Life expectancy for people with IPF is approximately 3-5 years post-diagnosis.  

In Douglas et al (2022) we reported the discovery of a first-in-class, highly selective furin inhibitor that was able to inhibit ENaC, restore airways surface liquid and normalise MCC using primary human CF bronchial epithelial cells.  Similar results have since been observed using COPD cells. The objective of this study is to see if further beneficial effects of furin inhibition in diseased lungs can be disclosed by investigating TGF-b-associated fibrotic pathways. This project will therefore, explore the impact of furin inhibition on inflammation and airway remodeling (fibrogenesis) as well as suppression of signaling pathways which could potentially reduce the muco-secretory/obstructive phenotype associated with lung disease. Importantly, these studies directly align to the strategic research interests of the Martin group and provides opportunity for the successful applicant to benefit from the significant expertise of the wider research group.  

  • Douglas LEJ, et al. (2023). Furin as a therapeutic target in cystic fibrosis airways disease. Eur Respir Rev. 3;32(168):220256. 
  • Douglas LEJ et al. (2022) A first-in-class, highly selective furin inhibitor BOS-318 rescues key features of cystic fibrosis airways disease. Cell Chem Biol. 29: 947-957.

The project will be primarily supervised by Professor Lorraine Martin, School of Pharmacy, Queen's University Belfast. Details and online profile are provided below.  

https://pure.qub.ac.uk/en/persons/lorraine-martin 

Normally applicants should have a 1st or 2.1 honours degree (or equivalent) in a relevant subject. Relevant subjects include Biochemistry, Pharmaceutical Biotechnology, Molecular Biology, Physiology, Biological/Biomedical Sciences or a closely related discipline. The School reserves the right to shortlist for interview only those applicants who have demonstrated high academic attainment to date. 

For international applicants: Evidence of an IELTS* score of 6.0, with not less than 5.5 in any component, or an equivalent qualification acceptable to the University is required.  

Postgraduate Research applicants must have applied to Queen’s, via the Direct Applications Portal. 

https://dap.qub.ac.uk/portal/user/u_login.php  

If you need further information on the project, please email Prof. Lorraine Martin at  

General information about the research activities at the School of Pharmacy, Queen's University Belfast are available at the link below:  

Professor Lorraine Martin_School of Pharmacy, QUB 

http://www.qub.ac.uk/schools/SchoolofPharmacy/Research/PostgraduatePositions/ 

http://www.qub.ac.uk/schools/SchoolofPharmacy/Research/ 

The successful applicant will join a well-resourced, multi-disciplinary team focussed on collaborative, translational research. The project will include use of gold standard ex vivo models of primary human airways epithelial cells cultured at air-liquid interface and will offer expert training in a wide range of biochemical, electrophysiological, protein biochemistry and imaging techniques. 

Students are expected to present at a minimum of one national and international meeting during their training and make a contribution to internationally excellent research outputs. Engagement with industry partners and participation in our on-going school’s outreach programme on lung health and/or science festivals will be encouraged. 


Biological Sciences (4) Medicine (26)

Funding Notes

Eligible students may compete for a Department of the Economy (DfE), Northern Ireland studentship which would be fully funded for three years, covering 100% of the UK/EU postgraduate tuition fee (currently £4,712 per annum) and a living stipend (currently £18,622 per annum). Applications from self-funding non-UK/EU nationals are also welcome, although, if successful, these applicants would, in addition to their living/maintenance costs, have to cover the additional costs associated with the international tuition fee (currently £25,600 per annum).

References

Chronic airways diseases to include protease biochemistry & airway physiology. lung, respiratory, airways, COPD, proteases, cell biology, molecular biology, biochemistry, electrophysiology

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