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Characterisation of new antimalarial drug targets, using state-of-the-art molecular approaches and CRISPR/Cas9 technology

  • Full or part time

    Prof S Krishna
  • Application Deadline
    Friday, March 23, 2018
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Malaria remains one of the major global killers of children but recently has been earmarked for eradication. For this to succeed, there is an urgent need for new antimalarial therapeutic strategies. This project aims to validate novel antimalarial drug targets that transport heavy metals such as iron and copper within the malarial parasite, Plasmodium. Using a range of classical and state-of-the-art molecular and cell biology approaches, targets will be characterised to determine their cellular location, transport activity and, most importantly, their essentiality. Those validated as drug targets will be used in drug screening assays to start the drug discovery process.

Heavy metals such as iron and copper are essential for malarial parasites to grow but can become toxic at high concentrations. Therefore, the parasite proteins that regulate heavy metal concentrations are potential antimalarial drug targets. Previously, we have characterised an iron transport protein that protects malarial parasites against the toxic effects of too much iron. Recent evidence has also suggested that heavy metal transport proteins are particularly important during malarial parasite development in the liver (a stage of infection before disease symptoms occur). We now wish to understand if heavy metal transport proteins can be targeted with novel drugs, which will have the ability to kill the parasites before they cause disease. This will be achieved by:

1. Identification of heavy metal transporters in the genomes of malarial parasites.

2. Production of parasite lines in which the transport proteins’ genes are disrupted, mutated or tagged, using newly available molecular approaches.

3. Production of yeast lines expressing parasite transporters, allowing characterisation in isolation.

4. Use of the novel parasites/yeast lines in growth assays to determine the effect of altering external heavy metal concentrations.

5. Use of cellular biology approaches to characterise transport proteins in both parasites and yeast (e.g. to determine localisation, expression levels, transport activity).

6. Development and use of drug screening assays, including the use of genetically encoded fluorescent heavy metal biosensors to provide the assay readout.

Together, these data will unlock our understanding of these critical malarial parasites transport proteins and validate them as novel antimalarial drug targets.

The project will be hosted by the Infection and Immunity Institute under the supervision of Dr Henry Staines and Professor Sanjeev Krishna.

Funding Notes

Each studentship will provide an annual stipend (amount as per MRC standard studentship rates) for three years, payment of fees at UK/EU rates, and an allowance for research and travel/conference of approximately £9,000 for the whole period of study.

Minimum qualification is a UK BSc (Honours) degree at 2:1 or EU equivalent and a minimum IELTS score of 6.5 overall (with no section less than 6.0) if required.

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