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Dissecting the role of protein disulphide isomerase in plasmodium, and targeting function to block malarial transmission

  • Full or part time
  • Application Deadline
    Wednesday, January 01, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

It is widely accepted that to achieve malaria eradication and long-term control, it will be necessary to use interventions that inhibit the transmission of parasites. A potential manner of achieving this is by targeting Plasmodium using transmission-blocking interventions (TBIs) against parasitic sexual stages. A current barrier to the development of TBIs, and furthermore, a current gap in the knowledge regarding parasitic cell biology, is that despite its essential nature to the completion of the lifecycle, the cellular and molecular mechanisms that underlie fertilisation remain largely opaque in Plasmodium.
In all living cells, the appropriate formation and cleavage of disulphide bonds between cysteine residues in secreted and membrane-anchored proteins is essential for function. Protein Disulphide Isomerase (PDI) is a multifunctional member of the thioredoxin superfamily of redox proteins. PDIs are traditionally known to be versatile enzymes with key roles in disulfide bond formation, isomeration and reduction. Little is known regarding the expression and function of PDI proteins in Plasmodium. Recent work, performed by us (http://biorxiv.org/cgi/content/short/411926v1) has demonstrated that PDI function, encoded by a single gene, is essential for malarial transmission. These results additionally emphasize the potential of anti-PDI agents to act as anti-malarials. However, the specific function of PDIs within Plasmodium is still unknown.
Based on this data, this project will aim to:
1). Elucidate the specific role of PDI in parasitic fertilisation/transmission.
2). Assess the mechanisms that underlie PDI-mediated activity throughout the parasitic lifecycle.
3). Identify novel anti-PDI transmission blocking interventions.

Funding Notes

Funding* will cover the student’s stipend at the current Research Council rate and University Fees. The studentships will be funded for three years in the first instance subject to eligibility**, with the possibility of additional funding in the fourth year depending on circumstances.

*The studentships are available to students who qualify for Home/EU fees

Applications from ineligible candidates will not be considered.

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References

1). http://biorxiv.org/cgi/content/short/411926v1
2). Delves MJ, Angrisano F, Blagborough AM. Anti-Malarial Transmission Blocking Interventions, Past, Present and Future. Trends in Parasitology 2018 Sep;34(9):735-746.
3). Fiona Angrisano, Katarzyna A. Sala, Dari F. Da, Yanjie Liu, Jimin Pei, Nick V. Grishin William J. Snell, Andrew M. Blagborough. Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum. Cell Reports. 2017. 21 (10): 2868-2878

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