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Integrating novel animal models and human genetic epidemiology to explore chronic inflammatory lung disease in vivo and test innovative anti-microbial strategies


   School of Biochemistry

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  Dr H Weavers, Prof D N Sheppard, Prof E Mahenthiralingam  No more applications being accepted  Competition Funded PhD Project (European/UK Students Only)

About the Project

Chronic inflammatory lung conditions are among the most frequent non-communicable diseases worldwide, affecting over 12 million people in the UK alone and 400 million people worldwide. These debilitating conditions (including chronic obstructive pulmonary disease, COPD, or cystic fibrosis, CF) are characterised by self-perpetuating cycles of lung damage, infection and inflammation. The persistent inflammatory response is more harmful than protective and a major driver of disease progression, causing dramatic destruction of healthy lung tissue that eventually results in respiratory failure and death (1,2). Despite considerable efforts to find new therapies, these debilitating conditions remain difficult to treat. There is also a disturbing increase in the incidence of antimicrobial resistance. Innovative treatments are urgently required, that both dampen inflammation and boost anti-microbial defences.

In this PhD project, we will integrate in vivo studies in Drosophila with human genetic epidemiology to dissect the cellular and molecular mechanisms driving these inflammatory conditions. We have already established Drosophila as an invaluable model to dissect fundamental mechanisms driving inflammation and tissue repair (3). Since Drosophila develop CF- and COPD-like pathologies, they represent an exciting invertebrate model to accelerate our understanding of chronic inflammatory lung disease.

Using state-of-the-art microscopy, we will explore disease progression in vivo and live-image the dynamic interactions between key cell types in the airway microenvironment. We will employ cutting-edge transcriptomic analysis on isolated cells to identify gene expression signatures associated with these diseases. This will be followed by advanced genomic editing (e.g. CRISPR) in Drosophila together with human genetic epidemiology to functionally characterise novel genes and explore their links to human disease. Finally, we will use our in vivo models as pre-clinical platforms to test novel therapeutic strategies, including novel antimicrobials.

The work has wide-ranging clinical relevance as our findings will be highly relevant to a diverse range of chronic inflammatory disease, such as asthma, cardiovascular disease and neurodegenerative conditions. This inter-disciplinary and cross-institutional PhD project is available on the “MRC GW4 BioMed Doctoral Training Program” and brings together a multi-disciplinary team of researchers from Bristol and Cardiff. This project offers a unique opportunity for training in a range of state-of-the-art techniques, including in vivo biology, state-of-the-art live imaging, genome editing (e.g. CRISPR), microbiology, transcriptomics, bioinformatics and molecular biology. 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: [Email Address Removed]

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

Collaborations:
Dr Jamie Duckers – Consultant Respiratory Physician (University Hospital Llandough)

Application deadline: 23 November 2020 by 5:00 pm. More information on how to apply and eligibility may be found on the DTP’s website: https://www.gw4biomed.ac.uk/doctoral-students/ (to apply click on the button "Institution website"). Please do NOT apply to the University of Bristol at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bristol.

Funding Notes

A full studentship will cover UK tuition fees, a training support fee and a stipend (£15,285 p.a. for 2020/21, updated each year) for 3.5 years.https://www.gw4biomed.ac.uk/doctoral-students/

Project information: https://www.gw4biomed.ac.uk/infection-immunity-and-repair-projects/
For more information about us, please see our lab website www.tissueresilience.com

References

(1) Brandsma et al (2020) Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine. J Pathol 250(5):624-635
(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