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EASTBIO The impact of PTP1B on neutrophil function and its role in susceptibility to fungal infection.


School of Medicine, Medical Sciences & Nutrition

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Prof H M Wilson , Prof M Delibegovic , Dr D MacCallum , Dr S Walmsley No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Professor Heather M Wilson (University of Aberdeen)
www.abdn.ac.uk/ims/profiles/h.m.wilson

Professor Mirela Delibegovic (University of Aberdeen)
www.abdn.ac.uk/ims/profiles/m.delibegovic

Dr Donna MacCallum (University of Aberdeen)
www.abdn.ac.uk/ims/profiles/d.m.maccallum

Professor Sarah Walmsley (University of Edinburgh)
https://www.ed.ac.uk/inflammation-research/people/principal-investigators/prof-sarah-walmsley

The aging process leads to physiological and immunological changes, rendering older patients more vulnerable to infection, particularly from fungal species and there is a growing need to better understand antifungal immunity. Neutrophils comprise approximately a 70% of circulating white blood cells and typically represent the first line of defence against fungal infection. However, the underpinning molecular mechanisms regulating these protective responses in neutrophils and how this impacts health and disease remain incompletely defined. This is important to understand to help develop more effective drugs for antifungal immunity in our aging population, and to predict whether the effects of new therapeutics will interfere with our natural immunity.

We have identified an important role for PTP1B as a key regulator of immune cell function. PTP1B is a protein tyrosine phosphatase that modulates central signalling pathways driven by extracellular stimuli, such as insulin, growth factors and inflammatory mediators. Our pivotal new research shows that PTP1B is critical in regulating susceptibility to fungal infection. However, whether it is important in direct killing of fungal pathogens by neutrophils or controlling the magnitude of fungal responses has not yet been reported. PTP1B is already a validated therapeutic target for age-associated diabetes, obesity, cardiovascular disease and cancer and inhibitors have reached early phase clinical trials. These inhibitors have health benefits, but how they influence neutrophil functions and susceptibility to fungal infection in these already vulnerable patients remains unexplored.

The key aim of this studentship is to fully characterise the regulation of neutrophil maturation, phenotype and function by PTP1B in infection. This studentship provides an exciting and unique opportunity to bring together a new supervisory team with expertise in a wide range of cutting edge technologies in neutrophil biology, cell signalling, ageing and fungal infection models to address important questions on the basic biological and molecular mechanisms by which PTP1B influences susceptibility to opportunistic pathogens. The specific research questions to be addressed are:

1. How are neutrophil responses to systemic fungal infection altered in animals treated with clinical PTP1B inhibitors?

2. What are the effects of clinical PTP1B inhibitors on human neutrophil functions in relation to infection and inflammation?

3. What are the key intracellular signalling pathways in immune cells that are controlled by PTP1B in response to infection by fungal pathogens and why would this alter infection susceptibility?

The student will receive extensive training in our well established infection models and the analysis of neutrophil recruitment to inflamed and infected organs and assaying their capacity to kill pathogens, primary neutrophil isolation and cell culture, neutrophil functional assays (time lapse phagocytosis imaging, degranulation, neutrophil extracellular trap (NET) formation, cytokine/reactive oxygen species output), novel intracellular signalling analysis techniques and flow cytometry, molecular biology and confocal microscopy imaging. A strong emphasis will be placed on training in experimental design and data analysis.

Application Procedure:

http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod at [Email Address Removed]. Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to [Email Address Removed].


Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

• Hünniger K, Kurzai O. Semin Cell Dev Biol. 2019 May;89:3-15.
• Través PG, et al. Cell Death Dis. 2014;5:e1125.
• Thompson D et al. Mol Metab. 2017; 6(8):845-853.


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