个人简介

Dr Hargreaves is the Module Leader for the Neurotoxity and Neuroscience module. He teaches on the modules Cell Signalling and Cancer and Research Methods and IT. Dr Hargreaves is the Chair of the College Research Ethics Committee.

研究领域

transglutaminase, neural stem cells

Areas of research interest include mammalian transglutaminases and proteomic analysis of neurotoxin-treated differentiating neural cell lines. Purification and characterisation of mammalian transglutaminases: A PhD project is currently underway to develop novel approaches to the purification of tissue transglutaminase from liver and brain tissue. This follows on from a recently completed PhD project, in which two forms of TG2 were detected in porcine brain and rodent cell lines, one of normal size (ca. 80 kDa) and the major form being lower than expected in molecular weight (ca. 55 kDa). The former was associated with mitochondria and the letter was the predominant form in the cytosol. Evidence suggests that the 50 kDa form is a truncated isoform of TG2 resulting from differential splicing. A novel method has now been developed to purify TG2 from liver and this will be applied to the purification of the truncated isoform in found porcine brain. This will allow studies of the kinetic properties of the short isoform with particular emphasis on its potential role as a toxicity target in certain chemically induced neuropathies. Proteomic analysis of neurotoxin-treated differentiating neural cell lines: This project aims to provide identification of novel markers of toxicity and involves a number of toxins of interest, including the organophosphate phenyl saligenin phosphate, the sheep dip pesticides diazinon and cypermethrin, the PD inducing agent MPTP and heavy metals such as methyl mercury chloride, with PhD students currently working on the last two subject areas. The main approach is to study mechanisms of toxicity at sub-lethal concentrations in differentiating cell lines representative of neuronal and glial phenotypes. End points for cell viability and differentiation include MTT reduction and neurite outgrowth, respectively. A range of potential molecular markers are being analysed in a targetted proteomic approach (e.g. Western blotting analysis of cytoskeletal proteins and cell signalling pathways involved in their regulation), whereas 2D-PAGE and MALDI-TOF approaches are being used to identify other changes. He has continued to collaborate with colleagues both internally and at the University of Derby, on the application of targetted and non-targetted proteomic approaches to the identification of biomarkers of toxicity, stress and food contamination. In the latter case he is a co-investigator (with Professor EE Billett) on a FSA-funded project to detect molecular markers in certain meat products.

近期论文

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Effects of sub-lethal neurite outgrowth inhibitory concentrations of chlorpyrifos oxon on cytoskeletal proteins and acetylcholinesterase. Harris W, Flaskos J, Hargreaves AJ, Sachana M and Nikolaidis E, Toxicology and Applied Pharmacology, 2011, 256, 330-336 Fipronil interferes with the differentiation of mouse N2a neuroblastoma cells. Harris W, Flaskos J, Hargreaves AJ, Sidiropoulou E, Sachana M et al, Toxicology Letters, 2011, 201 (1), 86-91 An extracellular transglutaminase is required for apple pollen tube growth. Di Sandro A, Del Duca S, Verderio E, Hargreaves AJ, Scarpellini A, Cai G, Cresti M, Faleri C, Iorio RA, Hirose S, Furutani Y, Coutts IG, Griffin M, Bonner PL, Serafini-Fracassini D, Biochem.J, 2010, 429 (2), 261-271 Diazinon oxon affects the differentiation of mouse N2a neuroblastoma cells. Sidiropoulou E, Sachana M, Flaskos J, Harris W, Hargreaves AJ, Woldehiwet Z, Archives In Toxicology, 2009, 83 (4), 373-380 Proteomic analysis of differentiating neuroblastoma cells treated with sub-lethal neurite inhibitory concentrations of diazinon: Identification of novel biomarkers of effect. Harris W, Sachana M, Flaskos J, Hargreaves AJ, Toxicology And Applied Pharmacology, 2009, 240 (2), 159-165