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Targeting the Unfolded Protein Response to Develop Novel Antimicrobial Therapies (Ref: SF20/APP/DOVER)

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Microbial pathogen resistance to antibiotics is an ever growing global concern. Antibiotics generally target microbial pathways important for survival and replication. Due to rapid bacterial cell division and the over use of antibiotics, these factors have combined to select for antibiotic resistant strains of important pathogenic micro-organisms.
Recently, research from my laboratory identified that intracellular bacteria such as Salmonella exploit host cell pathways to replicate and survive. We identified that Salmonella can induce the unfolded protein response (UPR) and exploit this pathway to enable their survival and intracellular replication. The UPR is a host cell defence mechanism which is triggered when excessive protein misfolding and/or synthesis perturbs the normal functioning of the endoplasmic reticulum (ER). In addition to Salmonella, Chlamydia have also been demonstrated to activate the UPR. Specifically, both Salmonella and Chlamydia can trigger lipid biosynthetic pathways via the UPR, raising the possibility that these group of intracellular pathogenic microorganisms can trigger common host cell pathways. Intriguingly, Listeria species which tend to occupy the cytosol, are sensitive to the UPR, which can lead to their elimination. Therefore, the above observations suggest that either inhibiting or activating the UPR can have effective antimicrobial effects depending on the cellular localisation of the pathogen.
The project aims to identify components of the UPR induced lipid biosynthetic pathway that are targeted by intracellular pathogens. In addition, the project aims to develop tools that can be used to inhibit and activate the UPR, with the view to developing these tools as anti-microbial agents. The approach proposed here is unique in that host biochemical pathways will be targeted, which could potentially reduce the emergence of antimicrobial resistance and provide a long term solution to antimicrobial resistance.
You will work with Dr Antony Antoniou and Associate Professor Lynn Dover in collaboration with Dr Janos Kriston-Vizi Laboratory for Molecular Cell Biology, Medical Research Council, University College London. You will develop infection models and screening assays, alongside the employment of the upgraded metabolomics facility to identify antimicrobial targets. You will verify the role of any potential target in the bacterial life cycle by using various gene targeting techniques. The project will identify new potential antimicrobial targets for future development.

Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed. Applications that do not include the advert reference (e.g. SF20/…) will not be considered.
Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March
Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.

For any informal inquiries please contact Associate Professor Lynn Dover ()

Funding Notes

Please note, this is a self-funded project and does not include tuition fees or stipend; the studentship is available to Students Worldwide. Fee bands are available at View Website . A relevant fee band will be discussed at interview based on project running costs

References

Antony N. Antoniou, Izabela Lenart, Janos Kriston-Vizi, Takao Iwawaki, Mark Turmaine, Kirsty McHugh, Sadfer Ali, Neil Blake, Paul Bowness, Mona Bajaj-Elliott, Keith Gould, Darren Nesbeth, Simon J Powis “Salmonella Exploits HLA-B27 and Host Unfolded Protein Responses to Promote Intracellular Replication” Annals of Rheumatic Disease 78, 74-82 2018
Antony N. Antoniou, Simon J. Powis and Janos Kriston-Vizi “High-content screening image dataset and quantitative image analysis of Salmonella infected human cells” BMC Research Notes in press 2020

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