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Live-imaging and genetic approaches to explore cross-talk between tissue damage, immune dysfunction and infection within novel animal models of cystic fibrosis


Project Description

Cystic fibrosis (CF) is a genetic disorder driven by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. These mutations result in an often-lethal respiratory disease affecting more than 10,500 people in the UK alone. Despite considerable progress in understanding the role of CFTR in epithelia, there is emerging evidence that CF patients have defects in several components of innate immunity that might drive disease progression (1).

CFTR functions as an anion channel that regulates salt and water movement across epithelial barriers. Mutations in CFTR cause a build-up of viscous mucus that not only obstructs the lungs, but leads to severe airway inflammation that fails to eradicate pulmonary pathogens. Indeed, many people with CF are chronically infected with bacteria such as Pseudomonas aeruginosa. Curiously, neutrophils from CF patients exhibit profound functional changes and can no longer migrate through the viscous mucus to capture bacteria (2). However, it remains unclear why CF patients exhibit these striking inflammatory defects.

In this PhD, we will investigate the molecular mechanisms underlying immune cell dysfunction in CF and how it promotes infection with P. aeruginosa, using state-of-the-art in vivo live-imaging and genetic approaches within Drosophila (3). We will follow the dynamic behaviour of inflammatory cells, analyse their ability to fight infection and employ cutting-edge transcriptomic analysis on isolated cells to identify gene expression signatures associated with CF. We will also use our in vivo models as a platform to test novel anti-microbial strategies for therapy. Finally, since CF is a multi-organ disease affecting diverse epithelial barriers, we will extend our models to explore the impact of CF-susceptibility genes on organs outside of the airways.

The work has wide-ranging clinical relevance as our findings will be highly relevant to other chronic inflammatory lung diseases, such as asthma and COPD (chronic obstructive pulmonary disease). This inter-disciplinary and cross-institutional PhD project is available on the “MRC GW4 BioMed Doctoral Training Program”. This project offers a unique opportunity for training in a range of state-of-the-art techniques, including in vivo biology, live imaging, genetic manipulation, transgenic line creation (e.g. CRISPR), microbiology, flow cytometry and transcriptomics. The Population Health studies will employ cutting-edge genetic epidemiology approaches. The student will be embedded in the vibrant research environment at the University of Bristol and have the opportunity to interact with our collaborators at the University of Cardiff and internationally (including ETH Zurich).

Main supervisor:
Dr Helen Weavers (University of Bristol); Email:

Secondary supervisors:
Prof Eshwar Mahenthiralingam (University of Cardiff)
Prof David Sheppard (University of Bristol)

International Collaborations:
Prof Sabine Werner (ETH Zurich)

For more information about us, please see our lab website http://www.tissueresilience.com!

Funding Notes

Link to project: View Website.

DEADLINE: 5.00 pm on Friday 25th NOVEMBER 2019
Please complete application to the GW4 BioMed MRC DTP for an ‘offer of funding’. You also need to make an 'offer to study' to your chosen institution(s) – details are on the website. View Website
A 3.5 year funded studentship by the GW4BioMed MRC Doctoral Training Partnership. Full UK/EU tuition fees, a stipend matching UK Research Council Minimum (£15,009 p.a. for 2019/20, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.

References

(1) Cohen & Prince (2012) Cystic fibrosis: a mucosal immunodeficiency syndrome. Nature Medicine 18:509-19
(2) Marteyn et al (2017) Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa. Front. Cell. Infect. Microbiol 7:243
(3) Weavers et al (2016) Creating a Buzz about Macrophages: The Fly as an In Vivo Model for Studying Immune Cell Behavior. Dev Cell 38:129-32

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