MRC DiMeN Doctoral Training Partnership: Identification of disease mechanisms and novel therapeutic targets in Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder affecting over 2 million people worldwide. Patients typically have sensory and motor dysfunction which is caused by either demyelination or axonal degeneration, or a combination of both. This project will investigate how loss of function mutations in mitofusin 2 (MFN2), which is the most common cause of axonal CMT, cause axonal degeneration. 

We previously developed a zebrafish model of MFN2 loss of function that develops a phenotype resembling axonal CMT (Chapman et al. Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish. PLoS One. 2013;8: e67276). To identify the mechanisms driving axonal degeneration in this model Dr Grierson’s team recently used RNA sequencing to identify dysregulated gene expression in the brain of the MFN2 mutant zebrafish. Dysregulated genes could be classified as members of 3 novel biological pathways.

Dr Barbaric has generated human induced pluripotent cells carrying pathogenic mitofusin 2 mutations. When differentiated into post-mitotic motor neurons these cells display hallmarks of CMT including disruption to mitochondrial transport. During this project you will investigate the involvement of the newly identified pathways in CMT, taking advantage of zebrafish and human motor neuron models.

We hypothesise that the dysregulated pathways identified in the zebrafish model are drivers of the CMT phenotype, and therefore that they are targets for therapeutic development in CMT. An important goal of your research will be to use a genetic approach (CRISPR/Cas9) to establish whether blocking key genes in the dysregulated pathways is sufficient to improve the CMT phenotype. These studies will pave the way for the identification of new therapeutic approaches to target these pathways in CMT patients.

Sheffield is a fantastic place to conduct Neuroscience research. You will be based across 2 institutes. The Sheffield Institute for Translational Neuroscience is research institute that brings together world-leading scientists and clinicians to find new ways to prevent and slow debilitating neurological diseases.  The Bateson Centre is an interdisciplinary grouping of scientists using zebrafish and other innovative models to understand human disease. It includes one of the largest zebrafish aquaria in Europe, and brings together approximately 40 research groups with shared interests in human disease.

Applicants should have a BSc or MSc in a biological science, and preferably experience of working in a research/laboratory setting.

For further information about the project please contact Dr Andy Grierson.

For more information about our current research please see

www.sheffield.ac.uk/medicine/people/neuroscience/andrew-grierson

www.sheffield.ac.uk/biosciences/people/bms-staff/academic/ivana-barbaric

www.sitran.org

www.sheffield.ac.uk/bateson

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 and how to apply can be found on our website:

https://bit.ly/3lQXR8A