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MRC DiMeN Doctoral Training Partnership: How do neurodegenerative mutations in kinesin-1 alter its structure, motility and cellular function?


Project Description

This studentship is focused on understanding the molecular basis of neurodegeneration through the study of molecular motors, with the aim of opening up new avenues for intervention in disease. You will be part of a new, multidisciplinary collaboration between the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield and the Astbury Centre at the University of Leeds.

Neurons form complex extended cellular structures. For example, motor neurons have cell bodies in the spinal cord, but extend axons down to the muscles of hands and feet. This length presents a problem for motor neurons, as the majority of newly synthesized protein is made in the cell body and then transported long distances down the axon to its site of use. Consequently, defects in transport are observed in many neurodegenerative conditions, including Alzheimer’s, Parkinson’s, Huntington’s and ALS, and understanding the mechanism of axonal transport is crucial to providing new avenues for therapeutic intervention. Kinesin motors power polarised long-range transport along the microtubules in neuronal axons. The goal of this project is to understand how disease causing mutations in kinesin disrupt the transport of specific axonal cargo.

This project represents a truly unique opportunity to integrate neuronal models of disease with biochemical & biophysical approaches and structural biology, exploring the molecular basis of transport by kinesin across systems and scales. The three research groups linked to this project encompass expertise in the structural, biophysical and neuronal cell biology of kinesin mediated axonal transport. You will be trained in advanced real-time imaging and analysis; neuronal cell biology (primary, stem cell and patient cell derived neuronal culture); biophysical approaches (in vitro reconstitution; single particle tracking); and structural biology. There is also potential to develop super-resolution microscopy (PALM/STORM) and CRISPR/Cas9 genome editing approaches to support the project. This research will provide fundamental insights into axonal transport, with translational outcomes for neurodegenerative diseases.

Creative individuals with an eye for detail are encouraged to apply. The successful applicant will be based in the Sheffield Institute for Translational Neuroscience, whilst working closely with all three labs involved. You will be supervised by Dr Alison Twelvetrees (Dept of Neuroscience, Sheffield), Dr Kurt De Vos (Dept of Neuroscience, Sheffield) and Dr Joseph Cockburn (Astbury Centre, Leeds). As an interdisciplinary project, applications from people from a diverse range scientific backgrounds are welcomed e.g. cell biology, biophysics, neuroscience, biochemistry, chemistry, structural biology and biomedical sciences. Interested applicants should contact Dr Twelvetrees to discuss the project:

Project supervisors
Dr Alison Twelvetrees; https://www.twelvetreeslab.co.uk/; https://twitter.com/dozenoaks; https://twitter.com/TwelvetreesLab
Dr Kurt De Vos; https://www.sheffield.ac.uk/neuroscience/staff/devos ; https://twitter.com/kdv1vdk
Dr Joseph Cockburn; http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=JJBC; https://twitter.com/CockburnLab

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 2019.

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

Twelvetrees, Alison E., Stefano Pernigo, Anneri Sanger, Pedro Guedes-Dias, Giampietro Schiavo, Roberto A. Steiner, Mark P. Dodding, and Erika L. F. Holzbaur. 2016. “The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1.” Neuron 90 (5): 1000–1015.

Cockburn, Joseph J. B., Sophie J. Hesketh, Peter Mulhair, Maren Thomsen, Mary J. O’Connell, and Michael Way. 2018. “Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3.” Structure 26 (11): 1486–98.e6.

Moller, Annekathrin, Claudia S. Bauer, Rebecca N. Cohen, Christopher P. Webster, and Kurt J. De Vos. 2017. “Amyotrophic Lateral Sclerosis-Associated Mutant SOD1 Inhibits Anterograde Axonal Transport of Mitochondria by Reducing Miro1 Levels.” Human Molecular Genetics 26 (23): 4668–79.

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