Molecular mechanisms of cognitive impairment caused by DMD gene mutations

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The PhD will be based in the Faculty of Science and Health, and will be supervised by Professor Darek Gorecki, Dr Rhiannon McGeehan and Dr Matt Parker. 

This project is part of an interdisciplinary programme of research led by Professors Darek Gorecki and Matt Guille and Drs Rhiannon McGeehan and Matt Parker.

DMD gene mutations result in Duchenne Muscular Dystrophy, which gave the gene its name. However, new data from our and other laboratories indicate that DMD mutations trigger downstream multi-system abnormalities going far beyond the mechanical instability in myofibres. These alterations are diverse and affect proliferation and signalling in specific cells, mitochondrial functions and metabolism and even oncogenesis. Moreover, cognitive deficits found in Duchenne patients are caused by distinctive molecular alterations resulting from DMD gene mutations in the brain cells. Given this increasing range of defects, identifying novel pathological mechanisms triggered by DMD mutations would advance our understanding of potential new roles of this largest human gene known in human health and disease. 

The strategic aim of the three interdisciplinary PhDs is to expand DMD research into new areas by exploiting novel findings and high quality preliminary data. The projects are mutually supporting, creating the critical mass, using several animal models offering cross-species validation of findings and access to the university infrastructure across the faculties. They also involve 10 external partners offering laboratory placements and an extensive range of expertise. Therefore, while the majority of work will be undertaken in Portsmouth, each PhD student will spend a short period at a collaborating laboratory. 

The scholarship covers tuition fees and an annual maintenance grant of £15,285 (UKRI 2020/21 rate) for three years. Scholarship recipients will also receive up to £3,000 for research project costs/consumables during the duration of the programme.

Mutations in the DMD gene cause the progressive neuromuscular disorder and also molecular alterations in neurons and astrocytes, which could explain the cognitive deficits commonly seen in Duchenne patients. Convergent lines of evidence point to an important role for DMD gene products (dystrophins) in regulating the molecular machinery in brain cells. However, less is known about the precise role of specific dystrophin isoforms in various neurons and glia in distinct brain regions. Unravelling mechanisms triggered by DMD mutations might help develop new treatments for this incurable and highly debilitating disease and help establish the physiological importance of DMD gene expression in brain cells. This project will exploit mouse models, distinguished by specific DMD gene mutations, in combination with advanced omics analyses to identify alterations of specific pathways and interaction networks and then confirm their impact using molecular methods (collaboration with Southampton University) and advanced microscopy (Portsmouth Zeiss Global Centre). In parallel, behavioural analyses in dystrophic mice and zebrafish will be performed. Using the latter model, individual brain cells will be visualised in vivo using the light sheet microscope (in collaboration with Exeter University). Subsequently, alterations found in these animal models will be compared with patients’ phenotypes. The PhD researcher will join a team using multidisciplinary approaches to analyse gene functions in health and disease. This project offers training in a range of techniques including proteomics, molecular biology, biochemistry, advanced microscopy and in vivo studies. 

How to apply

We’d encourage you to contact Professor Darek Gorecki (darek.gorecki@port.ac.uk) to discuss your interest before you apply, quoting the project code.

When you are ready to apply, you can use our online application form. Make sure you submit a personal statement, proof of your degrees and grades, details of two referees, proof of your English language proficiency and an up-to-date CV.  Our ‘How to Apply’ page offers further guidance on the PhD application process. 

If you want to be considered for this funded PhD opportunity you must quote project code PHBM4771020 when applying.