Role of DMD gene in development and function of white blood cells

Applications are invited for a fully-funded three-year PhD to commence in October 2020.

The PhD will be based in the Faculty of Science and Health, and will be supervised by Prof Darek Gorecki and Prof Matt Guille.

This project is part of an interdisciplinary programme of research led by Profs 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 work on this project will offer a broad-spectrum training including:
● Molecular and functional analyses of white blood cells ex vivo
● CRISPR/Cas9 gene editing and in vivo studies in Xenopus
● Multi-omics analyses

We have novel data that DMD mutations trigger multi-system abnormalities, including in the development and function of specific white blood cells. This project will investigate the role of DMD gene expression and the consequence of its dysfunction using a combination of methods and models. Bone marrow-derived cells from mice with different DMD gene mutations and the induced pluripotent stem cells from DMD patients differentiated into specific white blood cell types in vitro will be used in combination with proteomics to identify altered pathways and interaction networks. These findings will be validated using molecular and functional tests performed in collaboration with the laboratories of P. Pelegrin (BioMedical Research Institute of Murcia, Spain) and P. Ghezzi (Sussex University). The pathological consequences for the development and progression of dystrophy will be studied in mouse models using established molecular and microscopy methods. Unravelling novel abnormalities triggered by DMD mutations in white blood cells might help developing new therapeutic approaches for this condition. Furthermore, the Guille lab in the Portsmouth EXRC (https://xenopusresource.org/) has used CRISPR/Cas9 to mimic several genetic diseases, including DMD, in the Xenopus model. These DMD embryos will be used to assess the impact of DMD gene on haematopoiesis and white blood cell functions in vivo, in this ethically preferable and easily genetically modifiable model. 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 multi-omics dataset analyses, cell culture in vitro, advanced microscopy, CRISPR/Cas9 gene editing and in vivo studies in Xenopus and mouse models.

General admissions criteria
You’ll need an upper second class honours degree from an internationally recognised university or a Master’s degree in an appropriate subject. In exceptional cases, we may consider equivalent professional experience and/or qualifications. English language proficiency at a minimum of IELTS band 6.5 with no component score below 6.0.

Specific candidate requirements
You would have studied one of the following subjects: cell biology, biochemistry, developmental biology, pharmacology, immunology or a related molecular area and you would be keen to learn new things.

How to Apply
We’d encourage you to contact Prof Darek Gorecki ([Email Address Removed]) or Prof Matt Guille ([Email Address Removed]) 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 PHBM4791020 when applying.