Noncommunicable diseases, including chronic respiratory diseases, are responsible for 63% [36 million] of all deaths worldwide, making improved understanding and research an international priority. 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 the lung disease idiopathic pulmonary fibrosis (IPF) has been linked to damage and aberrant repair of the respiratory epithelium, driving fibrosis, morbidity and mortality. IPF is a chronic, progressive, interstitial lung disease, with median survival of 3-5 years from diagnosis. There are currently no effective treatments which increase lung function except transplantation, for which few patients are eligible. There is therefore a clear unmet need for new approaches to understand airway repair and disease. Recent work has led to a paradigm shift in understanding epithelial repair [Tetley et al. Nature Physics 2019 doi:10.1038/s41567-019-0618-1.], demonstrating that the ability of an epithelium to behave like a fluid, downstream of reduced mechanical tissue tension, is crucial for wound closure. Such work may be key to improved understanding of normal lung repair and lung diseases such as IPF.
This project will combine models of differentiated human airway cells, developed in Newcastle, with precise methods for studying injury and repair at the cellular level, developed in University College London. These will be applied to understand how the fluid status of the respiratory epithelium during repair influences its pro-fibrotic or anti-fibrotic crosstalk with fibroblasts and to identify potential treatment targets. This work will also involve a placement in Germany [Biberach an der Riss] with an industry partner Boehringer Ingelheim (BI). This is a highly innovative and novel project; the fluid status of the human airway epithelium has not been investigated during repair and may be key to understanding IPF pathophysiology and developing future treatments.
This is a multi-disciplinary collaboration combining human airway models and tissue culture, precise laser injury, quantitative bioimage analysis and biophysical measurements. To date this work has been limited to ‘discovery biology’ in Drosophila. The transfer of these approaches to differentiated air liquid interface human airway epithelial fibroblast co-cultures is a significant advancement. 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 fluid status of the repairing epithelium (through bioimaging, quantitative bioimage analysis and biophysical measurements) with its fibrotic/anti-fibrotic status (through measurement of markers of fibroblast-to-myofibroblast transition (FMT)). We will manipulate the epithelial barrier through siRNA knockdown of Claudin-18, a lung specific cell-cell adhesion protein involved in barrier function, and quantify changes in fluidity and fibrosis. 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. This work therefore has the potential to inform new approaches to treatment.
Chris Ward, Newcastle University https://www.ncl.ac.uk/icm/people/profile/chrisward.html#background
Rob Tetley, University College London https://www.ucl.ac.uk/lmcb/users/rob-tetley https://orcid.org/0000-0002-3322-6271
James Garnett, Boehringer Ingelheim Germany and Newcastle University https://www.linkedin.com/in/james-garnett-3038ba61/ https://www.ncl.ac.uk/icm/people/profile/jamesgarnett.html#background
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 can be found on our website: http://www.dimen.org.uk/
iCASE Award: Industrial partnership project:
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.
To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
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.