I studied for a BSc degree in Biochemistry at Bath University, followed by a PhD in Virology from Glasgow University and postdoctoral positions in research institutions in Glasgow and London. My research work was focused on transcription factor activation of gene expression in viral systems and cancer.
I then moved to the pharmaceutical industry, where I was involved in identifying genes from the human genome sequence which were suitable candidates for drug development. Since 2007 I have been working as a HCPC registered Clinical Scientist in diagnostic genetics in the NHS. I have worked in a number of clinical areas, ranging from haemostasis to metabolic disorders.
I was appointed as a lecturer at Sheffield Hallam University in May 2015.
I studied for a BSc degree in Biochemistry at Bath University, followed by a PhD in Virology from Glasgow University. My PhD project investigated how viral proteins activate gene transcription. I continued my research work investigating how transcription factors activate gene expression in cancer, working as a postdoctoral research associate at institutions in Glasgow and London.
I then moved to the pharmaceutical industry, working for three different pharmaceutical and biotech companies. The human genome sequencing project had just been completed. I was involved in several research projects trying to discover previously unidentified genes from the human genome sequence, which would be suitable targets for drug development.
Since 2007 I have been working as a HCPC registered Clinical Scientist in diagnostic genetics in the NHS, firstly in Manchester and more recently at Sheffield Children's Hospital. I have worked in a number of clinical areas, ranging from haemostasis to metabolic disorders. I was appointed as a lecturer at Sheffield Hallam University in May 2015, and I am teaching several subjects in biomedical sciences, including clinical chemistry, blood sciences, cancer and biology of disease.
Investigation of the molecular mechanisms of Vanishing White Matter Disease
Investigation of epigenetic mechanisms controlling gene transcription
Characterisation of the importance of eIF2B bodies in CACH/VWM disease
The initiation phase of protein synthesis is a key regulatory step in gene expression. One of the major control points in the translation initiation pathway is catalysed by the guanine nucleotide exchange factor eIF2B. In recent years a fatal human disease known as leukoencephalopathy with vanishing white matter (VWM) has been linked to mutations in all five subunits of eIF2B. The mechanism of pathogenesis of VWM is not clearly understood. The pathophysiology of VWM shows a central role for glial cells in the disease mechanism; however why oligodendrocytes and astrocytes are more affected than other cell types when eIF2B is required for all protein synthesis is unknown.
The key regulatory complex eIF2B and the G protein eIF2 co-localise to a specific cytoplasmic focus, termed eIF2B bodies. These bodies represent sites where the activity of eIF2B is controlled and regulated. This suggests that eIF2B bodies play an important role during active translation. We have recently identified a discrete localisation pattern for eIF2B subunits in glial cells. The effect of VWM mutations on the formation of these bodies in glial cells will be investigated to determine their functional impact.
We will use microscopy techniques such as FRET and FRAP to analyse eIF2B complexes.
Determination of the translational profile of VWM mutants in glial cells
Ribosome profiling is a method based on deep sequencing of ribosome-protected mRNA fragments. This allows the identification and quantification of the RNA molecules which are being actively translated within a cell. We aim to use CRISPR-cas9 technology to introduce mutant forms of the eIF2B subunits into glial cells. These cells will then be analysed using ribosome profiling, in order to determine the translational profile of glial cells in the presence and absence of common VWM mutations. This may highlight additional pathways underlying the mechanism of disease in these cells.
Dr L Crookes, Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust
Norris, K., Hodgson, R., Dornelles, T., Allen, K.E., Abell, B., Ashe, M.P., & Campbell, S.G. (2020). Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease. Journal of Biological Chemistry. http://doi.org/10.1074/jbc.RA120.014956
Little, L.D., Carolan, V.A., Allen, K.E., Cole, L.M., & Haywood-Small, S.L. (2020). Headspace analysis of mesothelioma cell lines differentiates biphasic and epithelioid sub-types. Journal of Breath Research, 14 (4), 046011. http://doi.org/10.1088/1752-7163/abaaff
Hodgson, R.E., Varanda, B.A., Ashe, M.P., Allen, K.E., & Campbell, S. (2019). Cellular eIF2B subunit localisation: implications for the integrated stress response and its control by small molecule drugs. Molecular biology of the cell, 30 (8), 933-1049. http://doi.org/10.1091/mbc.E18-08-0538
Hodgson, R., Allen, K.E., & Campbell, S. (2017). Characterisation of EIF2B bodies in vanishing white matter disease. JOURNAL OF NEUROCHEMISTRY, 142, 219-220.
Co-supervisor - Characterisation of the importance of eIF2B bodies in CACH/VWM disease and determination of the translational profile of VWM mutants in glial cells.