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Investigating the antimicrobial and immunomodulatory functions of β-defensins for AMR therapeutic use.

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  • Full or part time
    Dr J Dorin
    Prof Will Wood
    Prof D Dockrell
    Prof L Forrester
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

The newly established four-year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme will combine medical science and translational research projects with integrated and credited teaching in science communication, public engagement, patient involvement, data design and informatics, via established MSc courses and/or new Engagement for Impact courses. Our vision is to teach a generation of researchers equipped to address and solve real-world problems through excellent science and who have the engagement and impact skills we believe will give them an edge in their future careers.
https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme

This potential PhD project, selectable by successful applicants to this Programme, is supervised by Prof Julia Dorin (https://www.ed.ac.uk/inflammation-research/people/principal-investigators/professor-julia-dorin) at the Centre for Inflammation Research, with co-supervisors Prof Will Wood, Prof David Dockrell & Prof Lesley Forrester


Project Summary:
The alarming rise in antimicrobial resistance (AMR) means that the search for new antimicrobials with novel action is a priority area. Throughout eukaryotes, host peptides arise that have antimicrobial ability against invading pathogens and these are released upon pathogen challenge. One class of antimicrobial peptides (AMP) are defensins which are a multi-gene family in many species and in human have a copy-number variable cluster. These are variably potent AMP that are slow to develop antibiotic resistance, but also have additional functions including acting as promiscuous ligands and influencing innate immune cell function. This project seeks to validate Drosophila melanogaster as a genetically tractable and ethically acceptable system to determine the in vivo antimicrobial effect of defensin AMP against clinically important pathogens including multidrug resistant strains. We have obtained Crispr/Cas9 generated, AMP-deleted ( AMP) pathogen-sensitive flies, which allows both Gram positive and negative clinical, bacterial strains to infect embryo, larvae and adult flies. The student will determine bacterial killing of ESKAPE pathogens including those that exhibit multidrug resistance, by defensin-derived peptides alone or in combination with other AMP or antibiotics. In addition, live imaging will enable visualisation of the innate cellular response to pathogen challenge in real time and gain knowledge on the interactive function of mammalian AMPs with insect haemocytes (monocyte/macrophage equivalents). Finally, a macrophage culture model of human induced pluripotent stem cells (iPSC) macrophages will be used to complement the fly experiments and demonstrate translational relevance and therapeutic potential.

Engagement for Impact:
This project provides several possible areas for public engagement including (i) the danger of antimicrobial resistance; (ii) reducing use of vertebrates in experimentation and (iii) appreciation of macrophages in bacterial killing and wound resolution. The student will choose which area they feel most passionate about to take forward. Antimicrobial resistance is a major problem worldwide, is increasing in low and middle income countries and requires urgent, ongoing action to reduce inappropriate antibiotic use. This is particularly true in livestock as the growth advantage of animals treated with some antibiotics means farmers are loathe to stop their use particularly as high density livestock farming increases. The EU will ban the use of preventative antibiotics in 2020, but the UK government in its 5 year (2019-2024) national action plan did not confirm that it will follow suit. In addition, the UK is currently open to importing meats and dairy from countries that use higher levels of antibiotics than the UK. Student will apply to join Medical Research Foundation cohort of AMR students and use this to enhance engagement opportunities. Engagement activities should be giving the same strong message but levelled at various audiences eg. a game for primary children; an interactive play for secondary students (particularly those in rural areas such as East Lothian); talk and play for members of the public through “Lets talk about health” lecture series and other Science fairs; fact slide for biology teachers in local schools eg. Castlebrae high School; presentation to Members of Scottish Parliament eg. Mairi Gougeon (Minister for Rural Affairs and Natural Environment), as well as rural Scottish Westminster MPs to influence consideration of UK/Scottish policy on farming antibiotic use to influence policy.

Funding Notes

This is one of the potential projects in the University of Edinburgh College of Medicine and Veterinary Medicine’s new 4 year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme. Successful applicants will select their preferred PhD projects from the available options in discussion with proposed supervisors. Three studentships are available in the programme, providing full tuition fees (EU/UK rate only), stipend of at least £15,000 per year, £450 annual travel and conference allowance, dedicated engagement support grant of £1,500, and £5,000 annually towards research consumable costs.
Apply before 26th January 2020 at https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme



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