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MRC DiMeN Doctoral Training Partnership: From atoms to organoids: understanding how abnormal cilia cause a neurodevelopmental disorder


Project Description

Eukaryotic primary cilia are the “antennae” of eukaryotic cells that detect and integrate a wide variety of environmental signals essential for photosensation in the eyes, chemosensation in the nose, and mechanosensation in the kidneys. The base of the cilium regulates the trafficking of lipids and protein between the cilium and the cell body. Mutations in genes encoding ciliary proteins cause inherited disorders known as the ciliopathies, a major cause of childhood kidney failure and blindness. However, there are currently no cures and very few therapies that can reduce disease progression for this group of conditions. These inherited recessive conditions can, in principle, be corrected by gene-replacement, a therapeutic approach now undergoing Phase III clinical trials. This makes ciliopathies a top priority for further characterization of disease mechanism in order to fulfil the promise of personalized medicine approaches such as gene therapies.

You will study the disease mechanisms of mutations that cause an important ciliopathy called Joubert syndrome, characterised by neurodevelopmental defects, kidney cysts and blindness. Your work will focus on one ciliopathy protein CEP41 that is thought to modify tubulin which forms the microtubule “backbone” of the cilium. You will use state-of-the-art integrative structural biology approaches to understand the structure of this protein, what proteins it interacts with in the cilium, and how mutations in this protein cause disease at both the molecular and cellular levels.

Understanding cellular organisation is an exciting new frontier in biology, and the studentship provides opportunities for superb training in techniques that span structural biology and stem cell biology. The research also has direct medical relevance, informing the design of new targeted therapies. This work builds on successful projects between the Astbury Centre for Structural Molecular Biology, University of Leeds, and Leeds Institute of Medical Research. The Astbury Centre is a major hub for structural biology in the UK, with world-class facilities and a vibrant, highly interdisciplinary research environment. Both supervisors are involved in academic courses designed to teach doctoral students to follow cutting edge technical and conceptual advances in modern biology and to critically evaluate published data. Our laboratories provide hands-on training in many research skills to doctoral students. As part of this project, you will learn important methodologies in structural biology (including X-ray crystallography) in combination with molecular cell biology (microscopy and CRISPR-Cas9 genome editing. The project provides an exciting opportunity to start a research career by combining structural biology with molecular cell biology and medical genetics. You must demonstrate a strong background in biochemistry or molecular cell biology with a first degree in a relevant biomedical subject, and have the ability and ambition to develop a successful multidisciplinary research project.

Supervisors web pages:
Dr. Takashi Ochi: https://ochilab.org/
Twitter: @dr_takashi_ochi

Prof. Colin Johnson: https://medicinehealth.leeds.ac.uk/medicine/staff/478/professor-colin-a-johnson
Twitter: @johnsoncilialab

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 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 can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Buskin A, Zhu L, Chichagova V, Basu B, Mozaffari-Jovin S, …33 others… Grellscheid S-N, Johnson CA, Lako M (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 9:4234 doi: 10.1038/s41467-018-06448-y https://rdcu.be/85uN

Malicki J+, Johnson CA+ (2017). The cilium: cellular antenna and central processing unit. Trends Cell Biol. 27:126-140.

Ochi, T., Blackford, A. N., Coates, J., Jhujh, S., Mehmood, S., Tamura, N., Travers, J., Wu, Q., Draviam, V. M., Robinson, C. V., Blundell, T. L.. & Jackson, S. P. (2015). PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188

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