Investigating the Role and Regulation of Biomolecular Condensate Enabling Trypanosome Parasites Host Adaptation

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 Country: UK

Type: Ph.D. Project

Deadline: December 13, 2024

Details: https://www.dimen.org.uk/applications

 

About the Project

Applications are invited to a PhD project investigating RNA:protein (mRNP) condensates formed during pathogen differentiation and host adaptation. 

Working environment

Our team provides a collaborative environment in which the PhD student can thrive with individual support, expand their intellectual range and learn new techniques with the Technology Facility at their disposal. The PhD student will join a team of researchers in the York Biomedical Research Institute investigating cellular processes in parasites that cause African trypanosomiasis and leishmaniasis. York is internationally renowned  for Parasitology research, and is ranked in the Top 10 for both Research and Teaching. The first to attain (and retain) an Athena Swan Gold award in the UK, our Department provides a positive environment which allows all staff and students to contribute fully, flourish and excel.

Supervisor: Dr. Mathieu Cayla

Second supervisor: Dr. Pegine Walrad

Project 

Kinetoplastid parasites transition between insect and mammalian hosts, requiring quick adaptation through post-transcriptional gene regulation without extensive transcriptional control1. We recently demonstrated that quorum sensing of T. brucei in the mammalian bloodstream generates a specific and programmed hierarchy of biomolecular condensate assembly. These condensates have distinct components, including kinase regulators that contribute to downstream signalling of key pathways essential for life cycle progression2. 

The Aim of this project is to understand molecular regulation of parasite condensates by:

• Revealing the protein signature and architecture of biomolecular condensates.
• Investigating protein modifications regulating formation and stability of condensates.
• Identifying mRNAs critical to condensate formation.

Key responsibilities

The student will use super-resolution microscopy and cryoEM to visualise and quantify the extent and diversity of biomolecular condensate during the trypanosomes life cycle. Furthermore, the student will purify the different types of condensates using our established complementary approaches of UV crosslinking, protein tagging and proximity labelling. The student will identify modifications of proteins associated with these condensates via Mass Spectroscopy. They will use a kinome-wide RNAi library and perform single point mutations using CRISPr to investigate condensate regulatory mechanisms  during the parasite lifecycle. They will identify the mRNA and modifications associated with granules using next generation and nanopore direct sequencing. Finally, the student will use genetic and chemical tools to destabilise the condensate and examine the impact on parasite development.

Impact

The PhD student will be trained in the quantitative, computational and statistical analyses of -omics data. They will acquire critical transferable skills and professional resilience necessary for the success of this project and their future career. 

This research will reveal the unknown diversity, architecture and regulation of biomolecular condensates in an exceptional tractable model of medical importance. Understanding mRNP regulation will provide critical knowledge of how parasitic diseases persist. This will inform us on how such condensates enable parasites survival, transmission and disease progression. 

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.