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Sharpening the blunted neutrophil response to antimicrobial resistant fungal infection


Project Description

Life-threatening invasive fungal infection is a major health problem in the immunocompromised, and emerging drug resistance is a major threat to global health. Fungal pathogens, such as Candida, Cryptococcus and Aspergillus, are experts at immune evasion. Neutrophils - the most abundant white blood cell in humans - are vital in immunity to fungal infection, and optimising their function is a novel and powerful strategy to combat infection. The role of the neutrophils in fungal infection has been well studied in vitro but is difficult to translate to in vivo models of infection.

We have shown that if properly activated, neutrophils are very effective at controlling fungal infection, highlighting their potential as therapeutic targets. We are especially interested in low oxygen (hypoxia) signalling (via the transcription factor Hif-alpha). Infection sites are profoundly hypoxic and neutrophils have evolved to function in this environment. Targeting Hif-alpha therapeutically to activate neutrophils could be used against fungal infection, subverting antimicrobial resistance. You will use the transparent zebrafish embryo infected with Candida albicans and Cryptococcus neoformans to understand how hypoxia signalling might be targeted to treat fungal infection.

Using zebrafish models we already know that the two Hif-alpha variants, Hif-1alpha and Hif-2alpha, have opposing effects on neutrophil control of bacterial infection. In this project we aim to understand whether neutrophils can be molecularly ‘tuned’, by modulating Hif-1alpha and Hif-2alpha appropriately, to better kill invading fungi. Using cutting-edge molecular biology and fluorescence microscopy techniques you will address:
1. How Hif-alpha signalling is protective against fungal infection
2. How targeting different Hif-alpha variants can fine-tune neutrophil behaviour during fungal infection

This project synergises the expertise of a number of internationally leading groups at Sheffield Medical School, using techniques that are well-established in our groups that have so far produced exciting results and require an enthusiastic PhD student to take forwards. You will join a young and vibrant research lab (http://elkslab.weebly.com/) and you will be well trained in molecular biology and microscopy techniques, as well as writing and presenting your science. The research will take place in a newly refurbished bespoke zebrafish infection laboratory.

You should possess a high 2.1 or 1st class degree in a relevant biological degree. Relevant laboratory experience is not required, but a passion for tackling the growing problem of antimicrobial resistance is a must!

Funding Notes

Funding:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a first or upper second class honors degree or significant research experience.

PLEASE NOTE: This project is also open to other schemes within the University of Sheffield, which are currently being advertised.

References

Enquiries:
Interested candidates should in the first instance contact Dr Phil Elks ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Infection, Immunity & Cardiovascular Disease' as the department.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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