Role
Dr Hargreaves is an Associate Professor. He is Module Leader for the Masters level Cell Culture and Antibody Technology module (BIOL40032). He also teaches on several other modules including Research Methods & Bioethics (BIOL40102), Cell Signalling and Cancer (BIOL 33111), Toxicology (BIOL33211), Current Topics in Biochemistry (BIOL34013), Biochemical Techniques (BIOL25012) and Neuroscience (BIOL22151).
Dr Hargreaves is the Chair of the College Research Ethics Committee and carries out research mainly on the molecular basis of neurodegeneration and neurodevelopment.
Career overview
Dr Hargreaves gained extensive postdoctoral research experience in the study of cytoskeletal proteins in plant and animal cells, and in the molecular basis of chemically -induced peripheral neuropathies at the following institutions:-
Centro de Biologia Molecular, Universidad Autonoma de Madrid, Spain (1982-86)
John Innes Instutute, Norwich, UK. (1986-89)
Department of Pharmacology & Therapeutics, University of Liverpool, Liverpool, UK (1989-92)
He then obtained the following academic teaching posts:-
Temporary Lecturer, Department of Biochemistry, University of Birmingham, Birmingham, UK (1992-93)
Lecturer/Senior Lecturer, Department of Life Sciences, Nottingham Trent University, Nottingham , UK (1993-2006)
Reader/Associate Professor in Biochemistry, School of Science & Technology, Nottingham Trent University, Nottingham , UK (2006-present)
Research areas
Through collaborations with internationally respected researchers at NTU, the rest of the UK and abroad, Dr Hargreaves has used differentiating mammalian neural cell lines (N2a, C6, PC12, SH-SY5Y) and , more recently, human neural progenitor stem cells to study mechanisms of neural development, neurotoxicity and neurodegeneration.
A major aim of this work is to identify novel biomarkers of neurotoxicity or neurodegenerative disease that will not only help to establish the mechanism(s) involved but will also identify potential targets for therapeutic intervention.
His overall strategy is to study the effects of neurotoxins (such as organophosphates, MPTP, beta amyloid peptide and heavy metals) on differentiating nerve cells using a range of cellular and molecular approaches. His research group has identified several novel biomarkers of neurotoxicity, and promoters of neurite outgrowth and neuroprotection. For example, in the case of organophosphate toxicity, in studies of neurite outgrowth and retraction his group has identified novel changes in cytoskeletal and associated signalling proteins and their corresponding changes at the gene level. The inhibition of neuronal and glial differentiation was found to be associated with increased activity of histone deacetylase, suggesting OP-induced changes at the epigenetic level, the mechanism of which is of great interest to the group.
Dr Hargreaves' interest has recently moved into the interdisciplinary research area of 3D culture using nanofibre scaffolds to develop more human-relevant models of neural development, neurodegeneration and nerve repair. For example, in collaboration with Dr Luigi de Girolamo and Professor Bob Stevens, he is involved in the development of a nanofibre-based cellular model of chemically-induced parkinsonism (Manuscript submitted for publication). Dr Hargreaves is also very keen to develop similar models for the study of Alzheimer's disease by identifying novel biomarkers of beta amyloid toxicity.
In addition to studies of neurotoxicity, he is also involved in collaborative work using cellular models of hepatotoxicity (HepG2, HepaRG), cardiotoxicity (H9c2 and mesenchymal stem cell models), testicular toxicity (TM3 and TM4 cell lines) and immunotoxicity (THP-1 cells). For example, he collaborates with Dr John Dickenson on projects to study the cardiotoxic effects of organophosphates and the role of tissue transglutaminase in neuronal and cardiomyocyte development and cytoprotection (see recent publications). He is currently supervising a PhD student who is looking at the effects of OPs on the activity of enzymes in the blood clotting cascade in human plasma and on the synthesis and secretion FXIIIa from THP-1 cells (1 PhD project).
In collaboration with Dr Chris Lloyd Mills at NTU he has studied the effects of pesticides and heavy metals on the aquatic organism Gammarus pulex (2 PhD projects; manuscripts in preparation)
Dr Hargreaves is open to PhD students, academic or commercial collaboration in any of the above or related areas.
Expertise available includes high content imaging (speciality in neurite outgrowth), immunoblotting and ELISA (including cell ELISA), indirect immunofluorecsence, microtitre plate enzyme assays (MTT reduction, Cell Titer Blue, dual fluorescence live-dead assay, cholinesterases, transglutaminases, HDAC, LDH, caspase, etc.), RT-PCR, protein characterisation by 2D-PAGE and (in collaboration with colleagues at NTU) mass spectrometry,
Dr Hargreaves has supervised 31 PhD students to completion (12 as Director of Studies and 19 as Co-Supervisor). He is currently supervising 8 PhD students (1 as DoS and 8 as Co-S).
Opportunities to carry out postgraduate research towards an MPhil / PhD or MSc by research exist in all the areas identified above and in associated interdisciplinary areas. Further information may be obtained from the NTU Graduate School.
External activity
- Member of the Biochemical Society
- External Examiner for 8 PhD students including 2 Euro-doctorates
- External Examiner and panel member for the defence of a thesis for the degree of Doctor of Pharmacy (University of Lille2, November 2011)
- External Examiner MSc Molecular Toxicology, Aston University (2009-13)
- Associate Editor, Environmental Toxicology and Pharmacology
- Member of the Extended Advisory Group for Molecular Approaches in Toxicology (OECD)
Recent presentations:
- Organophosphate induced delayed neurotoxicity. Workshop on “Adverse Outcome Pathways in Neurotoxicity”. EU Joint Research Centre, Ispra, Italy (March 2013).
- 'Adverse outcome pathway for organophosphate induced delayed neuropathy' (SOT, Phoenix Arizona, March 2014)
- The potential of proteomics in regulatory toxicology. OECD meeting of the Extended Advisory Group for Molecular Approaches in Toxicology (OECD Conference Centre, Paris, June 2017)
- Current international research collaboration: Professor J Flaskos of the Aristotle University of Thessaloniki.
Sponsors and collaborators
Dr Hargreaves' research has been conducted with the collaboration, funding and / or support of:
- British Council
- Consejo Superior de Investigaciones Cientificas
- Wellcome Trust
- Royal Society
- Nuffield Foundation
- Defra
- EU funding: EU Framework V, and 'Working with You'
- A variety of sponsors of international PhD students
Current external collaborations include the University of Liverpool and the Aristotle University of Thessaloniki,
Publications
Selected publications
- Harris W, Sachana M, Flaskos J, Hargreaves AJ, (2009) Proteomic analysis of differentiating neuroblastoma cells treated with sub-lethal neurite inhibitory concentrations of diazinon: Identification of novel biomarkers of effect. Toxicology And Applied Pharmacology, 240 (2), 159-165
- Flaskos, J., Nikolaidis, E., Harris, W., Sachana, M., and Hargreaves, A.J. (2011) Effects of sub-lethal neurite outgrowth inhibitory concentrations of chlorpyrifos oxon on cytoskeletal proteins and acetylcholinesterase. Toxicology and Applied Pharmacology, 256, 330-336
- Almami, I., Dickenson, J.M., Hargreaves, A.J. and Bonner, P.L.R. (2014) Modulation of transglutaminase 2 activity in H9c2 cells by PKC and PKA signalling: A role of transglutaminase 2 in cytoprotection. British Journal of Pharmacology 171, 3946-3960.
- Felemban, S.G., Garner, A.C., Smida F.A., Boocock, D.J., Hargreaves, A.J. and Dickenson, J.M. (2015) Phenyl saligenin phosphate induced caspase on mitotic and differentiated rat H9c2 cardiomyoblasts. Chemical Research in Toxicology, 28, 2179-2191.
- Sindi, R.A.,Harris, W., Arnott, G., Flaskos, J., Lloyd Mills, C (2016) Chlorpyrifos- and chlorpyrifos oxon-induced neurite retraction in pre-differentiated N2a cells is associated with transient hyperphosphorylation of neurofilament heavy chain and ERK 1/2. Toxicology and Applied Pharmacology, 308, 20-31.
- Vyas, F.S., Nelson C.P., Freeman, F., Boocock, D.J., Hargreaves, A.J., Dickenson, J.M. (2017) β2-adrenoceptor-induced modulation of transglutaminase 2 transamidase activity in cardiomyoblasts. Eur J Pharmacol 813, 105-121.
- Algarni, A.S., Hargreaves, A.J. and Dickenson J.M. (2018) Activation of transglutaminase 2 by nerve growth factor in differentiating neuroblastoma cells: A role in cell survival and neurite outgrowth. Eur J Pharmacol 820, 113-129.
For full list click 'Go to Alan Hargreaves publications' link above.