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MRC DiMeN Doctoral Training Partnership: Understanding dysregulated repair in lung disease through precise laser injury and quantitative analysis of live cell behaviours in a human airway epithelial model


MRC DiMeN Doctoral Training Partnership

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Dr C Ward , Dr R Tetley , Dr J Garnett No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Bioinformatics Biophysics Medicine Pathology

About the Project

Background.
The lungs are uniquely exposed to the external environment due to their function. Along with a life sustaining atmosphere, this environment can contain diverse agents of injury ranging from microbiology through to pollutants. Lung repair is therefore a key mechanism of homeostasis, vital to health and disease but which is incompletely understood.
In particular the initiation and progression of Idiopathic pulmonary fibrosis (IPF) have been linked to damage and aberrant repair of the respiratory epithelium, driving fibrosis, morbidity and mortality. Recent work has led to a paradigm shift in understanding epithelial injury and repair [Nature Physics 2019]. This demonstrates that the ability of an epithelium to behave like a fluid, downstream of a reduction in mechanical tissue tension, is crucial for wound closure.

Objectives.
This application will combine differentiated models of human airway cells with precise methods for studying injury and repair at the cellular level. This will be applied to understand how the status of the respiratory epithelium in injury and repair influences its pro-fibrotic or anti-fibrotic crosstalk with fibroblasts and potential treatment targets.

Novelty
The fluid status of the human airway epithelium has not been investigated and may be key to understanding IPF pathophysiology and future treatments.

Timeliness
Currently no standard of care therapies for chronic lung diseases, including IPF, directly address injury/repair processes in the respiratory epithelium, despite its central role in disease initiation and progression.

Experimental Approach
This is a multi-disciplinary collaboration between an early career fellow, the PI and Boehringer Ingelheim. The fellow has developed a laser based injury model, coupled quantitative bioimage analysis and biophysical measurements. To date this work has been limited to ‘discovery biology’ in Drosophila. The transfer of this model to differentiated air liquid interface human airway epithelial fibroblast co-cultures is a significant advancement and deliverable goal. Preliminary co-culture data generated at BI support the hypothesis that epithelial injury can induce myofibroblast production and can be manipulated. We aim to correlate the status of the epithelium in injury/repair through bioimaging, quantitative bioimage analysis and biophysical measurements, together with its fibrotic/anti-fibrotic status through measurement of markers of fibroblast-to-myofibroblast transition (FMT). To manipulate the epithelial barrier, we will measure/model these parameters following siRNA knockdown of Claudin-18, a lung specific cell-cell adhesion protein involved in barrier function. Targeting cell-cell adhesion is rational, as increased cell-cell adhesion has been shown to modulate wound closure and tissue fluidity via a change in epithelial mechanical properties.

Non-academic partner: Dr James Garnett, Head of Respiratory Epithelial Research at Boehringer Ingelhiem, Germany (and Associate Senior Lecturer, Newcastle University). Dr Garnett has developed epithelia-fibroblast co-culture models that will be utilised during the project, and will thus assist the PhD student with learning these cultures as well supporting the student with translational/therapeutic-based project outcomes.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:
https://bit.ly/3lQXR8A


Funding Notes

iCASE Award: Industrial partnership project

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: https://bit.ly/3kPNjoJ

Studentships commence: 1st October 2020.
Good luck!

References

1. Tissue fluidity promotes epithelial wound healing. Robert J. Tetley, Michael F. Staddon, Davide Heller, Andreas Hoppe, Shiladitya Banerjee, Yanlan Mao Nat Phys. (2019) doi:10.1038/s41567-019-0618-1.

2. Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients.
Powell J, Garnett JP, Mather MW, Cooles FAH, Nelson A, Verdon B, Scott J, Jiwa K, Ruchaud-Sparagano MH, Cummings SP, Perry JD, Wright SE, Wilson JA, Pearson J, Ward C, Simpson AJ.
Am J Respir Crit Care Med. 2018 Aug 1;198(3):340-349.

3. Human lung fibroblast-to-myofibroblast transformation is not driven by an LDH5-dependent metabolic shift towards aerobic glycolysis. Schruf E, Schroeder V, Kuttruff CA, Weigle S, Krell M, Benz M, Bretschneider T, Holweg A, Schuler M, Frick M, Nicklin P, Garnett JP, Sobotta MC. Respir Res. 2019 May 9;20(1):87. doi: 10.1186/s12931-019-1058-2.
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