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Post-transcriptional regulation of transferrin receptor expression in Trypanosoma brucei

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

The goal of this project is to understand how Trypanosoma brucei controls expression of iron regulatory proteins in response to changes in intracellular iron. T. brucei is a unicellular eukaryotic pathogen that infects humans and animals in sub-Saharan Africa. The parasites live extracellularly in blood and tissues where they interact with their host obtaining essential micronutrients such as iron for survival. Iron is an essential micronutrient functioning as a critical co-factor for numerous important reactions, but in the presence of oxygen iron can be very toxic - creating the need for very tight regulation of free iron levels. In mammalian cells this regulation is achieved by iron regulatory proteins (IRP) binding iron responsive elements (IRE) to control expression levels of major components of the iron acquisition pathway, such as the transferrin receptor (TfR). However, how this task is achieved in T. brucei is completely unknown. Interestingly, T. brucei has a surface protein that functions as a transferrin receptor (TbTfR), and expression levels of this protein is also modulated by iron availability. Previous work indicates that T. brucei lacks the canonical IRP/IRE iron-based regulatory system.

We have performed genome-wide transcriptome and proteomic studies to identify factors whose expression levels are modulated when trypanosomes are depleted of iron. The PhD project will use a combination of biochemical, cell biology and molecular genetic approaches (e.g. CRISPR-Cas9 genome editing, flow cytometry, immunofluorescence microscopy, RNA interference and overexpression) to study the function of these proteins, and investigate whether differences exist in iron-regulatory pathways between mammalian hosts and trypanosome parasites using omics approaches.

For more info visit our lab website: https://tiengwe.wixsite.com/website

Funding Notes

This PhD project is offered on a self-funded basis. It is open to all applicants with funding or those applying to funding sources. We are happy to provide support in drafting applications. Candidates must be able to meet admission criteria and tuition fee requirements of our department.

There is also a potential for a China Scholarship Council fellowship with the following eligibility criteria:
Be a Chinese national
Meet the requirements of the CSC – View Website
Hold an unconditional offer to study for a PhD at the Imperial College London

References

- Steverding, D., et al. (1995) Transferrin-binding protein complex is the receptor for transferrin uptake in Trypanosoma brucei, J Cell Biol 131, 1173-1182.
Fast B, Kremps K, Boshart M, & Steverding D (1999) Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei. Biochem. J. 342:691-696.

- Tiengwe, C., et al. (2017) Controlling transferrin receptor trafficking with GPI-valence in bloodstream stage African trypanosomes, PLoS Pathog 13, e1006366.

- Tiengwe, C., et al. (2018). ER-associated degradation and disposal of misfolded GPI-anchored proteins in Trypanosoma brucei, Molecular Biology of the Cell, 29:2359-2507

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