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Click here to search FindAPhD.com for PhD studentship opportunities(MBRC) Deciphering the lung immunomatrix to define patient classification and treatment in pulmonary disease
Prof T Hussell, Prof J Vestbo
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
This PhD proposal is built on promising evidence that patients with inflammatory lung disease can be characterised better by taking new approaches in biomarker analysis. An ideal biomarker is specific for the disease, discriminates between different disease severities and can be sampled by non-invasive methods.
This project will examine extracellular matrix products (ECM) and cleaved immune receptors in nasal swabs and sputum samples from patients with Chronic Obstructive Pulmonary Disease (COPD) to facilitate patient categorisation, treatment and response.
Turnover of the ECM is a hallmark of tissue injury and repair and, as such, can indicate disease severity and its characteristics. Fragments of extracellular matrix proteins form the matrisome, many constituents of which influence a multitude of processes including inflammation, immune responses and wound repair. In addition, the natural process of an immune response results in the release of soluble ectodomains of immune stimulatory receptors by proteases as an effective method of resolving inflammation. The type of receptors discovered relate to the type of immune cell present, their numbers and state of activation. A classic example is the release of soluble TNF receptor trimers that sequester TNF-α preventing activation of membrane-bound receptors. Other examples include shed L-selectin that binds PSGL1 on endothelial cells curtailing cell adhesion and JAM-A that binds LFA-1 on leukocytes impeding transmigration. The TAM receptor AXL that recognises apoptotic cells, OX40 ligand that facilitates T cell survival and TREM2 that curtails inflammation, are other examples of receptors that are cleaved.
In preliminary experiments we have proven that these soluble receptors and matrix proteins are detectable using flow cytometric and mass spectrometry methods in nasopharyngeal swabs and sputum samples from patients with COPD. The PhD student will continue this research to discover a) combinations of matrix and cleaved receptors that distinguish COPD of varying severity, b) indicators of COPD with or without co-existing pulmonary infection, c) whether this approach can be used to distinguish bacterial or viral complications in COPD and d) new soluble characteristics of the disease that could be targeted therapeutically.
The student will work with Tracy Hussell who is Director of the Manchester Collaborative Centre for Inflammation Research and Professor of inflammatory disease and Jørgen Vestbo who is the specialty lead for Respiratory Medicine and Professor of Respiratory Medicine.
This project will examine extracellular matrix products (ECM) and cleaved immune receptors in nasal swabs and sputum samples from patients with Chronic Obstructive Pulmonary Disease (COPD) to facilitate patient categorisation, treatment and response.
Turnover of the ECM is a hallmark of tissue injury and repair and, as such, can indicate disease severity and its characteristics. Fragments of extracellular matrix proteins form the matrisome, many constituents of which influence a multitude of processes including inflammation, immune responses and wound repair. In addition, the natural process of an immune response results in the release of soluble ectodomains of immune stimulatory receptors by proteases as an effective method of resolving inflammation. The type of receptors discovered relate to the type of immune cell present, their numbers and state of activation. A classic example is the release of soluble TNF receptor trimers that sequester TNF-α preventing activation of membrane-bound receptors. Other examples include shed L-selectin that binds PSGL1 on endothelial cells curtailing cell adhesion and JAM-A that binds LFA-1 on leukocytes impeding transmigration. The TAM receptor AXL that recognises apoptotic cells, OX40 ligand that facilitates T cell survival and TREM2 that curtails inflammation, are other examples of receptors that are cleaved.
In preliminary experiments we have proven that these soluble receptors and matrix proteins are detectable using flow cytometric and mass spectrometry methods in nasopharyngeal swabs and sputum samples from patients with COPD. The PhD student will continue this research to discover a) combinations of matrix and cleaved receptors that distinguish COPD of varying severity, b) indicators of COPD with or without co-existing pulmonary infection, c) whether this approach can be used to distinguish bacterial or viral complications in COPD and d) new soluble characteristics of the disease that could be targeted therapeutically.
The student will work with Tracy Hussell who is Director of the Manchester Collaborative Centre for Inflammation Research and Professor of inflammatory disease and Jørgen Vestbo who is the specialty lead for Respiratory Medicine and Professor of Respiratory Medicine.
Funding Notes
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Applicants must be from the UK/EU and funding covers fees/stipend for three years commencing September 2018. Applicants may contact the Primary Supervisor directly with any questions. Online applications must be submitted, select 'Manchester BRC' as the programme - for more information on how to apply please visit https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mbrc-studentships/
Applicants must be from the UK/EU and funding covers fees/stipend for three years commencing September 2018. Applicants may contact the Primary Supervisor directly with any questions. Online applications must be submitted, select 'Manchester BRC' as the programme - for more information on how to apply please visit https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mbrc-studentships/
References
1.Garton, K.J., Gough, P.J. & Raines, E.W. Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J. Leukoc. Biol. 79, 1105–1116 (2006).
2.Weiss G, Lai C, Fife ME, Grabiec AM, Tildy B, Snelgrove RJ, Xin G, Lloyd CM, Hussell T. Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors. Mucosal Immunol. 2017 Jul;10(4):1021-1030.
3.Smalley, D.M. & Ley, K. L-selectin: mechanisms and physiological significance of ectodomain cleavage. J. Cell Mol. Med. 9, 255–266 (2005).
4.Koenen, R.R. et al. Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases. Blood 113, 4799–4809 (2009).
2.Weiss G, Lai C, Fife ME, Grabiec AM, Tildy B, Snelgrove RJ, Xin G, Lloyd CM, Hussell T. Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors. Mucosal Immunol. 2017 Jul;10(4):1021-1030.
3.Smalley, D.M. & Ley, K. L-selectin: mechanisms and physiological significance of ectodomain cleavage. J. Cell Mol. Med. 9, 255–266 (2005).
4.Koenen, R.R. et al. Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases. Blood 113, 4799–4809 (2009).
