Is this PhD Project for you?
This PhD Project suits a student seeking multidisciplinary training that impacts global infectious disease. This project is at the interface of molecular biology, epigenetics and structural biology and explores novel strategies to combat parasitic disease. You will train with world-leading experts and develop state-of-the-art skills in RNA biology, parasite genetics, bioinformatic analyses and structural biochemistry.
About the Project:
Background: Leishmania parasites are the causative agent of leishmaniasis, the 2nd deadliest parasitic disease next to malaria with >1M new cases annually. Leishmania infect and destroy human immune cells. T.brucei parasites devastate livestock in central Africa. No vaccine is currently available against either parasite and treatments are toxic with growing resistances. New strategies are desperately needed. Kinetoplastid parasite gene regulation is overwhelmingly dependent upon RNA binding protein (RBP) function. Importantly, the majority of RBPs are conserved between Leishmania and T.brucei, but not in animals. Targeting essential RBP:RNA (RNP) complexes for disruption could promote broad-spectrum treatment strategies against multiple parasitic diseases. This project focuses on the potential for targeted disruption of parasite RNP complexes as a novel combative strategy.
Objectives: Targeted disruption of RNPs is the primary treatment strategy against HIV, and recent evidence suggests it could be exploited to combat leishmaniasis1.
We seek to:
1. Identify which specific interactions enable parasite RNP complex stability, essential to survival, mammalian infection and virulence.
2. Use predictive and available RNP structures to determine molecular sites vulnerable to disruptive oligo/peptide therapies.
3. Prioritise, design and produce oligos and peptides to disrupt parasite RNP complexes.
4. Test disruptive potential in parasite culture conditions both in vitro and ex vivo in macrophage infections.
Novelty: Kinetoplastid parasites represent powerful unicellular model systems to investigate therapeutic RNP disruption strategies. Gene regulation is overwhelmingly posttranscriptional, with unusually high reliance upon parasite-specific RBPs for essential processes. To date, no combative strategy targets RNP complexes or utilises oligos or peptides as therapeutics.
Timeliness: Leishmaniasis is a growing global threat without a vaccine or suitable treatments. T.brucei devastates African livestock. New intervention strategies are desperately needed and RNPs are both essential to parasite viability and divergent from mammalian hosts. This project combines parasite cell, molecular and structural biology to investigate a novel anti-parasite combative strategy. The supervisory team has world-leading expertise in parasite genetics, RNP interactions and structural biology. Ongoing MRC-funded investigations will complement proposed objectives.
Experimental Approach:
- Molecular interaction analyses will be used to identify potentially targetable regions of protein:RNA (RNP) interactions.
- Recombinant oligos and peptides will be designed, produced and tested for impact upon RNP interactions using cellular, structural, biochemical and biophysical analyses.
- Functional studies of interactions and parasite viability both in vitro and ex vivo with training in genetic, biochemical and molecular analytic techniques, parasite culture and leukocyte infection assays.
Research Environment:
The York Biomedical Research Institute (YBRI) is a state-of-the-art research centre dedicated to mentoring in molecular medicine and combating global disease.
More about the Supervisors:
Dr. Pegine Walrad https://www.york.ac.uk/biology/research/infection-immunity/peginewalrad/
Dr. Michael Plevin https://www.york.ac.uk/biology/research/biochemistry-biophysics/michael-plevin/
Dr. Joana Correia Faria https://www.york.ac.uk/biology/our-staff/joana-r-correia-faria/
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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
Continue with Facebook
