Allen, K Elizabeth - Sheffield Hallam University - Department of Biosciences and Chemistry

个人简介

I studied for a BSc degree in Biochemistry at Bath University, followed by a PhD in Virology from Glasgow University and post-doctoral 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.

研究领域

Biomolecular Sciences Research Centre 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.

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Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, Klaffke S, Joyce CJ, Dhawan A, Hadzic N, Mieli-Vergani G, Kirk R, Elizabeth Allen K, Nicholl D, Wong S, Griffiths W, Smithson S, Giffin N, Taha A, Connolly S, Gillett GT, Tanner S, Bonham J, Sharrack B, Palotie A, Rattray M, Dalton A, Bandmann O. (2013) A genetic study of Wilson's disease in the United Kingdom. Brain 136(Pt 5):1476-87. doi: 10.1093/brain/awt035. Searle C, Andresen BS, Wraith E, Higgs J, Gray D, Mills A, Allen KE, Hobson E. (2013) A large intragenic deletion in the ACADM gene can cause MCAD deficiency but is not detected on routine sequencing. JIMD Rep. 11:13-6. doi: 10.1007/8904_2013_216. Temple R, Allen E, Fordham J, Phipps S, Schneider HC, Lindauer K, Hayes I, Lockey J, Pollock K, Jupp R. (2001) Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes. Am J Respir Cell Mol Biol. 25(4): 425-33. Morris, L., Allen, K. E. and La Thangue, N. B. (2000) Regulation of E2F transcription by cyclinE/cdk2 kinase mediated through p300/CBP coactivators. Nature Cell Biol. 2(4):232-9. De la Luna, S., Allen, K. E., Mason, S. L. and La Thangue, N. B. (1999) Integration of a growth-suppressing BTB/POZ domain protein with the DP component of the E2F transcription factor. EMBO J.18(1) 121-28.