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Ubiquitin-like modifications underlying Cell Differentiation and Biology in Trypanosomes

   Biomedical and Life Sciences

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  Dr Federico Rojas Martinez, Dr P McKean  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Post-translational protein modifications are major regulators of eukaryotic cell functions and include modifications by attachment of polypeptides such as ubiquitin and ubiquitin-like proteins (UBLs). Nedd8 is a UBL that activates the Cullin-E3 ubiquitin-ligases (CRLs ) responsible for substrate ubiquitination for protein degradation/activity modification.

Trypanosomes remain major pathogens in sub-Saharan Africa, causing human African trypanosomiasis and livestock ‘nagana'. The infection threatens an estimated 60 million people and about 50 million cattle. Every year, it causes about 3 million deaths in cattle while approximately 35 million doses of trypanocidal drugs are administered. The economic losses in cattle production alone are in the range of US$ 1.0 - 1.2 billion. Transmission of Trypanosoma brucei between mammalian hosts by the tsetse fly vector involves a crucial life cycle differentiation in the mammal, from replicative slender cells into quiescent stumpy forms, which dominate chronic infections and are needed for transmission. During this differentiation process, changes in the cell proteome occur, but how this process is regulated has not yet been addressed. My preliminary analysis shows an increase in protein neddylation when cells differentiate into stumpy forms, both in terms of the number of neddylated proteins and in the amount of neddylation on selected proteins. This analysis also revealed the existence of a large number of non-Cullin neddylated substrates, given their molecular weights detected by western blot. Furthermore, I also demonstrated that knock-outs of known regulators of neddylation are critical for this developmental transition.

In this project, you will help develop our understanding of the molecular and cellular mechanisms underlying NEDD8 signalling using an established in vivo model and combining CRISPR/Cas9 knock-outs and endogenous tagging, quantitative proteomics and proximity-labelling techniques. You will gain broad expertise in trypanosome biology, cell-signalling regulation and proteomics.

Your research will provide broader understanding of developmental regulation mechanisms influenced by NEDD8 and allow us to decipher which molecular mechanisms are conserved, unique or new to pathogenic parasites. In the longer term, such findings could be transformative from a treatment perspective. 

Application process: Applications should be made in writing to the lead supervisor, Dr Federico Rojas ([Email Address Removed]). You MUST include the following

1.     CV (max 2 A4 sides), including details of two academic references

2.     A cover letter outlining your qualifications and interest in the studentship (max 2 A4 sides)

Funding Notes

The full-time studentships are tenable up to 3 years full-time (subject to satisfactory progress) and will cover the cost of tuition fees at Home/EU rates alongside a stipend in line with the UK Research Council is payable.
It is expected the successful applicant will commence 1st October 2022.
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