Yr Athro Adrian Harwood
PhD, FRSB
Technical Director of the Neuroscience and Mental Health Research Institute
- harwoodaj@cardiff.ac.uk
- +44(0) 29 2068 8492
- 3.33, Adeilad Hadyn Ellis, Heol Maendy, Caerdydd, CF24 4HQ
- Sylwebydd y cyfryngau
Trosolwg
I am neuro-cell biologist based in the Neuroscience and Mental Health Research Institute (NMHRI), and School of Biosciences. I have extensive experience in molecular signalling systems and cell analysis in neuronal and model cell systems.
My current work focuses on the molecular and cellular interactions that underlie genetic risk for psychiatric conditions and dementia. Current projects focus on cell signalling, synaptic function, neurodevelopment and epigenetic mechanisms, and how they modulate neuronal and glial cell function and drug sensitivity. I am using human stem cell and CRISPR technologies to create new model systems for the study of neuropsychiatric disorders and their pharmacological analysis, and have developed human cell-based assays using Multi-Electrode Array techniques to monitor altered neuronal network activity arising from genetic mutation. In doing so, my work aims to both develop new therapeutic strategies and provide basic insight into the cellular mechanisms underlying mental health.
Bywgraffiad
Following my BA in Zoology from the University of Oxford, I investigated gene targeting by mitotic homologous recombination in cultured mammalian cells at the University of Edinburgh under the supervision of Chris Bostock, being awarded a PhD in 1988.
My further research focused on the study of signal transduction processes in the context of cell biology. Initially, I held a Research Fellowships at the ICRF Clare Hall Laboratories (1988-1991) in the group of Jeff Williams. During this period, I pioneered the study of cAMP-dependent protein kinase in Dictyostelium, establishing the basic role of this important kinase in spatial and temporal control during development. I also established a number of key technologies for Dictyostelium research, including the use of lacZ marker genes. I was awarded a MRC Post-doctoral Fellowship at the MRC Laboratory of Molecular Biology, Cambridge, (1992-1994) in the group of Rob Kay. Here, I carried out the first REMI mutagenesis screens outside the US, leading to discovering the essential role of GSK-3 in cell and developmental biology of Dictyostelium.
In 1995 I was awarded a Wellcome Trust Senior Biomedical Fellowship and established my own research group at the MRC Laboratory for Molecular Cell Biology (LMCB), holding a staff position in the Dept of Biology at University College London. I was promoted to Reader in 2001 and a personal chair in 2003. During this period, I continued to study GSK-3 signalling in Dictyostelium and developed an international reputation in the area of Wnt signaling. I discovered the first beta-catenin and the existence of adherens junctions outside the metazoa, published in Nature. In addition, my Cell paper on GSK-3 was a cornerstone for the discovery that lithium inhibits GSK-3. I have continued to investigate the role of lithium on cellular signaling pathways, investigating both GSK-3 and inositol phosphate signaling in both Dictyosteliumand neurons. My 2002 Nature paper is a seminal paper in the field of psychopharmacology, showing that inositol phosphate signaling is a common target of the majority of mood stabilizers.
In 2005, I moved to the School of Biosciences at Cardiff University, and was a co-founder of the University's Neuroscience and Mental Health Research Institute (NMHRI). I have continued to develop my research in on the neurocellular basis of psychiatric disorders and the mechanism of action of mood stabilizers, building a new group focussed on human iPSC.
Aelodaethau proffesiynol
I am a member of the Collegium Internationale Neuro-Psychopharmacologicum (CINP), and a Fellow of the Royal Society of Biology (FSB), associate Editor of Molecular Biotechnology and an academic editor for Scientific Reports and an editorial board member of Cells.
Safleoedd academaidd blaenorol
Within the School of Biosciences, I was Group Leader of the Molecular Cell Biology Research Group (2005-2007) and Neuroscience (2011) was Head of Innovation, Partnership and Engagement from 2009-2013. I am currently co-Director of Research, and a co-Director of NMHRI.
Ymrwymiadau siarad cyhoeddus
I am a regular speaker at the BAP, CINP and ACNP, and a member of the CINP and Fellow of the Society of Biology (FSB).
Cyhoeddiadau
2022
- Robinson, J. et al. 2022. The association of neurodevelopmental abnormalities, congenital heart and renal defects in a Tuberous Sclerosis Complex patient cohort. BMC Medicine 20, article number: 123. (10.1186/s12916-022-02325-0)
- Chapman, G. et al. 2022. Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome. Molecular Psychiatry 27, pp. 819-830. (10.1038/s41380-021-01182-2)
- Stewart, B. et al. 2022. The genetic architecture underlying prey-dependent performance in a microbial predator. Nature Communications 13(1), article number: 319. (10.1038/s41467-021-27844-x)
- Sanders, B. et al. 2022. Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants. Nature Communications 13(1), article number: 27. (10.1038/s41467-021-27601-0)
2021
- Gruenheit, N. et al. 2021. Mutant resources for functional genomics in Dictyostelium discoideum using REMI-seq technology. BMC Biology 19(1), article number: 172. (10.1186/s12915-021-01108-y)
2020
- Oliva-Teles, N. et al. 2020. Rare pathogenic copy number variation in the 16p11.2 (BP4–BP5) region associated with neurodevelopmental and neuropsychiatric disorders: a review of the literature. International Journal of Environmental Research and Public Health 17(24), article number: 9253. (10.3390/ijerph17249253)
- Alsaqati, M., Heine, V. M. and Harwood, A. J. 2020. Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation. Molecular Autism 11, article number: 80. (10.1186/s13229-020-00391-w)
- Davis, B., David, F., O’Regan, C., Adam, M., Harwood, A., Crunelli, V. and Isles, A. 2020. Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency. Brain and Neuroscience Advances 4 (10.1177/2398212820928647)
- Drakulic, D. et al. 2020. Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD. Molecular Autism 11(1), article number: 42. (10.1186/s13229-020-00343-4)
- Perry, C. J. et al. 2020. A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models. British Journal of Pharmacology 177(4), pp. 912-928. (10.1111/bph.14892)
2019
- Plumbly, W., Brandon, N., Deeb, T. Z., Hall, J. and Harwood, A. J. 2019. L-type voltage-gated calcium channel regulation of in vitro human cortical neuronal networks. Scientific Reports 9, article number: 13810. (10.1038/s41598-019-50226-9)
- Harwood, J. C., Kent, N. A., Allen, N. D. and Harwood, A. J. 2019. Nucleosome dynamics of human iPSC during neural differentiation. EMBO reports 20(6), article number: e46960. (10.15252/embr.201846960)
- Nadadhur, A. G. et al. 2019. Neuron-glia interactions increase neuronal phenotypes in tuberous sclerosis complex patient iPSC-derived models. Stem Cell Reports 12(1), pp. 42-56. (10.1016/j.stemcr.2018.11.019)
2018
- Harwood, A. and Baldwin, A. 2018. Dictyostelium. In: Reference Module in Life Sciences 2018. The curated reference collection in Life Sciences Elsevier, (10.1016/B978-0-12-809633-8.13033-X)
- Cocorocchio, M. et al. 2018. Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum. Disease Models & Mechanisms 11, article number: 32375. (10.1242/dmm.032375)
2017
- Platt, J. L., Kent, N. A., Kimmel, A. R. and Harwood, A. J. 2017. Regulation of nucleosome positioning by a CHD Type III chromatin remodeler and its relationship to developmental gene expression in Dictyostelium. Genome Research 27, pp. 591-600. (10.1101/gr.216309.116)
2016
- Falk, A. et al. 2016. Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Molecular Psychiatry 21(9), pp. 1167-1179. (10.1038/mp.2016.89)
2015
- Tarrés, M. et al. 2015. Biological interaction of living cells with COSAN-based synthetic vesicles. Scientific Reports 5, article number: 7804. (10.1038/srep07804)
2014
- Tarrés, M., Canetta, E., Viñas, C., Teixidor, F. and Harwood, A. J. 2014. Imaging in living cells using νB–H Raman spectroscopy: monitoring COSAN uptake. Chemical Communications 50(25), pp. 3370-3372. (10.1039/c3cc49658a)
2013
- Platt, J. L., Rogers, B. J., Rogers, K. C., Harwood, A. J. and Kimmel, A. R. 2013. Different CHD chromatin remodelers are required for expression of distinct gene sets and specific stages during development of Dictyostelium discoideum. Development 140(24), pp. 4926-4936. (10.1242/dev.099879)
- Harwood, A. J., Forde -Thomas, J., Williams, H., Samereier, M. and Müller-Taubenberger, A. 2013. Aberrant spindle dynamics and cytokinesis in Dictyostelium discoideum cells that lack glycogen synthase kinase 3. European Journal of Cell Biology 92(6-7), pp. 222-228. (10.1016/j.ejcb.2013.05.001)
- Fox, M. et al. 2013. Phosphorylation of the Actin Binding Protein Drebrin at S647 Is Regulated by Neuronal Activity and PTEN. PLoS ONE 8(8), article number: e71957. (10.1371/journal.pone.0071957)
2011
- Harwood, A. J. 2011. Prolyl oligopeptidase, inositol phosphate signalling and lithium sensitivity. CNS & Neurological Disorders - Drug Targets 10(3), pp. 333-339. (10.2174/187152711794653779)
- Perrins, R. D. et al. 2011. Doing more with less: a method for low total mass, affinity measurement using variable-length nanotethers. Analytical Chemistry 83(23), pp. 8900-8905. (10.1021/ac2012569)
2010
- Teo, R. M. M., Lewis, K., Forde, J. E., Ryves, W. J., Reddy, J. V., Rogers, B. J. and Harwood, A. J. 2010. Glycogen synthase kinase-3 is required for efficient 'Dictyostelium' chemotaxis. Molecular Biology of the Cell 21(15), pp. 2788-2796. (10.1091/mbc.E09-10-0891)
- King, J. et al. 2010. Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes. PLoS ONE 5(6), article number: e11151. (10.1371/journal.pone.0011151)
- Rey, S. M., Harwood, A. J., Povazay, B., Hofer, B., Unterhuber, A. and Drexler, W. 2010. Mutant and wild type cell chemotaxis in 3D and 4D with ultrahigh- resolution optical coherence tomography.. Presented at: Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XIV, San Francisco, CA, USA, 25-27 January 2010 Presented at Izatt, J. A., Fujimoto, J. G. and Tuchin, V. V. eds.Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XIV. Proceedings of SPIE Vol. 7554. Bellingham, WA: SPIE pp. 505-509., (10.1117/12.843244)
2009
- Kasry, A., Borri, P., Davies, P. R., Harwood, A. J., Thomas, N., Lofas, S. and Dale, T. C. 2009. Comparison of methods for generating planar DNA-modified surfaces for hybridization studies. ACS Applied Materials & Interfaces 1(8), pp. 1793-1798. (10.1021/am9003073)
- Rey, S. M., Považay, B., Hofer, B., Unterhuber, A., Hermann, B., Harwood, A. J. and Drexler, W. 2009. Three- and four-dimensional visualization of cell migration using optical coherence tomography. Journal of Biophotonics 2(6-7), pp. 370-379. (10.1002/jbio.200910027)
- Rey, S. M., Harwood, A. J., Povazay, B., Hofer, B., Unterhuber, A., Hermann, B. and Drexler, W. 2009. Visualization of 3D cell migration using high speed ultrahigh resolution optical coherence tomography. Presented at: Optics in tissue engineering and regenerative medicine III, San Jose, CA, USA, 24 January 2009 Presented at Kirkpatrick, S. J. and Wang, R. eds.Optics in Tissue Engineering and Regenerative Medicine III, 24 January 2009, San Jose, CA, USA. Proceedings of SPIE Vol. 7179. Bellingham, WA: SPIE - International Society for Optical Engineering pp. 505-509., (10.1117/12.809178)
- Shimshoni, J. A., Dalton, E. C., Watson, P. D., Yagen, B., Bialer, M. and Harwood, A. J. 2009. Evaluation of the effects of propylisopropylacetic acid (PIA) on neuronal growth cone morphology. Neuropharmacology 56(4), pp. 831-837. (10.1016/j.neuropharm.2009.01.014)
- King, J. et al. 2009. The mood stabiliser lithium suppresses PIP3 signalling in 'Dictyostelium' and human cells. Disease Models & Mechanisms 2(5-6), pp. 306-312. (10.1242/dmm.001271)
- Teo, R. M. M., King, J., Dalton, E. C., Ryves, W. J., Harwood, A. J. and Williams, R. S. B. 2009. Ptdins (3,4,5)P-3 and inositol depletion as a cellular target of mood stabilizers. Biochemical Society Transactions 37(5), pp. 1110-1114. (10.1042/BST0371110)
- Peineau, S. et al. 2009. A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases. Molecular Brain 2(1), article number: 22. (10.1186/1756-6606-2-22)
2008
- Cho, J., King, J., Qian, X., Harwood, A. J. and Shears, S. B. 2008. Dephosphorylation of 2,3-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport-Luebering glycolytic shunt. Proceedings of the National Academy of Sciences of the United States of America 105(16), pp. 5998-6003. (10.1073/pnas.0710980105)
- Harwood, A. J. 2008. Dictyostelium development: a prototypic Wnt pathway?. In: Vincan, E. ed. Wnt Signaling., Vol. 2. Methods in Molecular Biology Vol. 469. New York, NY: Humana Press, pp. 21-32., (10.1007/978-1-60327-469-2_2)
- Harwood, A. J. 2008. Monitoring patterns of gene expression in Dictyostelium by beta-galacotsidase staining. In: Vincan, E. ed. Wnt signaling- Pathway models., Vol. 2. Methods in Molecular Biology Vol. 469. Totowa, N.J.: Humana, pp. 33-37.
- Harwood, A. J. 2008. Use of the Dictyostelium stalk cell assay to monitor GSK-3 regulation. In: Vincan, E. ed. Wnt Signaling., Vol. 469. Methods in Molecular Biology Springer, pp. 39-43., (10.1007/978-1-60327-469-2_4)
- Dale, T. C., Harwood, A. J. and Borri, P. 2008. Method of measuring the affinity of biomolecules. EP1949104A2 [Patent].
2007
- Shaltiel, G., Dalton, E. C., Belmaker, R. H., Harwood, A. J. and Agam, G. 2007. Specificity of mood stabilizer action on neuronal growth cones. Bipolar Disorders 9(3), pp. 281-289. (10.1111/j.1399-5618.2007.00400.x)
- Strmecki, L. et al. 2007. Proteomic and microarray analyses of the Dictyostelium Zak1-GSK-3 signaling pathway reveal a role in early development. Eukaryotic Cell 6(2), pp. 245-252. (10.1128/EC.00204-06)
2006
- Shimshoni, J. A. et al. 2006. The effects of central nervous system-active valproic acid constitutional isomers, cyclopropyl analogs, and amide derivatives on neuronal growth cone behavior. Molecular Pharmacology 71(3), pp. 884-892. (10.1124/mol.106.030601)
2005
- Ryves, W. J., Dalton, E. C., Harwood, A. J. and Williams, R. S. B. 2005. GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid. Bipolar Disorders, pp. 260-265. (10.1111/j.1399-5618.2005.00194.x)
2004
- Schilde, C., Araki, T., Williams, H., Harwood, A. J. and Williams, J. G. 2004. GSK-3 is a multi-functional regulator of Dictyostelium development. Development 131(18), pp. 4555-4565. (10.1242/dev.01330)
2002
- Harwood, A. J., Kim, L. and Kimmel, A. 2002. Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates cell fate choice. Developmental Cell, pp. 523-532. (10.1016/S1534-5807(02)00269-1)
- Williams, R. S. B., Cheng, L., Mudge, A. W. and Harwood, A. J. 2002. A common mechanism of action for three mood-stabilizing drugs. Nature, pp. 292-295. (10.1038/417292a)
- Fraser, E. et al. 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277(3), pp. 2176-2185. (10.1074/jbc.M109462200)
- Williams, R. S. B., Cheng, L., Mudge, A. W. and Harwood, A. 2002. A common mechanism of action for three mood stabilizing drugs. Nature 417(6886), pp. 292-295. (10.1038/417292a)
Neurodevelopmental disorders (NDDs), such as schizophrenia and autism spectrum disorders (ASD) are common, chronic psychiatric conditions that contribute substantially to the global disease burden. Genetic studies are now identifying a series of genes that increase the risk of developing these conditions. Furthermore, considerable genetic risk also exists for the major conditions of bipolar disorder and dementia. My research aims: to establish the neurocellular phenotypes arising from these genetic changes; to understand the mechanisms underlying the origins mental illness and to develop new therapeutic strategies. Current projects focus on epigenetic, neurodevelopmental and synaptic mechanisms associated with disease aetiology and drug action.
We are investigating three types of mechanism across a range of cell types differentiated from human induced pluripotent stem cells (iPSC). A number of epigenetic modulators have been associated with ASD, schizophrenia and epilepsy. We are studying the effects of EHMT1 and the CHD family of proteins on neurodevelopment, gene regulation and synaptogenesis. In addition to structural and metabolic process, certain lipids and fatty acids are essential for cell signalling. We are investigating the interaction of lipids and the bipolar risk gene Fatty Acid Desaturase 2 (FADS2) and their effects on stem cell proliferation, neurodevelopment and synaptic function.
Genes encoding synaptic proteins that mediate glutamate and GABA signalling are strongly associated with neuropsychiatric disorders. We are using combinations of CRISPR, genomic and Multi-Electrode Array (MEA) technology in human stem cells to create new model systems for the study of these disorders and novel pharmacological intervention.
Current grants
- Wellcome Trust Strategic Award (WTSA): DEFINE: Defining Endophenotypes from Integrated Neurosciences.
- The Waterloo Foundation: Future minds
- MINDDS (Maximising research Impacts for Neurodevelopmental Disorders). European COST Action
- Cardiff University-Takeda Industrial Partnership
Collaborations
- Jeremy Hall, NMHRI, Cardiff University
- John Atack, Medicines Discovery Institute (MDI), Cardiff University
- Julie Williams, UK Dementia Research Institute (DRI) Centre, Cardiff University
- Vivi Heine, VU University Medical Center, Amsterdam
- Patrick Sullivan, Karolinska Institutet, Stockholm.
Ymgysylltu
quick brown fox....
