Hallett, Maurice - Cardiff University

个人简介

My research is currently within the Division of Infection and Immunity and is focussed on neutrophil behaviour and signalling at the individual cell level.. I established the Neutrophil Signalling Group within Cardiff University Medical School with the aim of using novel techniques to understand and influence the activity of these cells which are important in inflammatory disease. For a number of years, the Neutrophil Signalling lab has studied signalling in living human neutrophils. In this way, the link between the chemical change within the neutrophil and its responses have been observed and the effect of experimental interventions established. This has necessitated the invention of some novel micro-manipulation and imaging techniques. The individual cell approach, however, has revealed an insight into how neutrophils are able to carry out their work-programme in a co-ordinated and effective manner. It also points towards therapeutic targets which may be beneficially manipulated in inflammatory disease. We have established that an important Ca2+ “read-out” is the Ca2+ activated protease, mu-calpain activation. Since the action of the protease may be long-lived (or irreversible), this would provide a molecular memory of previous Ca2+ signalling within the cell. This has become an important focus for progress towards understanding the link between Ca2+ signals and physiological or pathological responses by the neutrophils.

研究领域

The neutrophil represents an unusual cell type within the body, in which there is a degree of autonomy of cell-response decision-making. In some respects, the possible response outcomes are “primitive” cell behavioural responses, e.g. cell shape change, phagocytosis and chemotaxis, whereas in other respects there are more sophisticated outcomes, e.g. apoptosis, gene expression and oxidase assembly. Individual neutrophils must perform a program of activity in the correct sequence, location and timing (based on their repertoire of behaviours) to produce effective anti-bacterial protection. Yet, many of the same steps lead to pathological and chronic inflammatory diseases, such as rheumatoid arthritis. The goal of our research is to understand the signalling and integration of these separate behaviours. While this is a worthy goal in itself, as it contributes to our fundamental knowledge of cellular processes; it underpins the larger aim of understanding and ultimately preventing the aberrant behaviour of these cells during inflammatory diseases. At present, the Group has focused on three aspects of neutrophil signalling (i) cytosolic free Ca2+ signals (ii) PIP2 generation and signalling and (ii) calpain translocation and activation. We have built up the necessary equipment for measurement, manipulation and imaging chemical changes in individual living neutrophils, and solved some of the difficult problems which arise when working with these cells.

近期论文

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Adams, S.et al. 2015. Conformationally restricted calpain inhibitors. Chemical Science 6(12), pp. 6865-6871. (10.1039/c5sc01158b) pdf Campbell, J. S. and Hallett, M. 2015. Active calpain in phagocytically competent human neutrophils: electroinjection of fluorogenic calpain substrate. Biochemical and Biophysical Research Communications 457(3), pp. 341-346. (10.1016/j.bbrc.2014.12.113) Adams, S.et al. 2014. The structural basis of differential inhibition of human calpain by indole and phenyl α--mercaptoacrylic acids. Journal of Structural Biology 187(3), pp. 236-241. (10.1016/j.jsb.2014.07.004) pdf Lewis, K.et al. 2014. Minimal impact electro-injection of cells undergoing dynamic shape change reveals calpain activation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1843(6), pp. 1182-1187. (10.1016/j.bbamcr.2014.02.020) Miller, D.et al. 2013. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future?. Future Medicinal Chemistry 5(17), pp. 2057-2074. (10.4155/fmc.13.172) Dewitt, S., Francis, R. J. and Hallett, M. B. 2013. Ca2+ and calpain control membrane expansion during rapid cell spreading of neutrophils. Journal of Cell Science 126(20), pp. 4627-4635. (10.1242/jcs.124917) Midgley, A.et al. 2013. Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation Is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. Journal of Biological Chemistry 288(21), pp. 14824-14838. (10.1074/jbc.M113.451336) Francis, R. J., Kotecha, S. and Hallett, M. B. 2013. Ca2+ activation of cytosolic calpain induces the transition from apoptosis to necrosis in neutrophils with externalized phosphatidylserine. Journal of Leukocyte Biology 93(1), pp. 95-100. (10.1189/jlb.0412212) Adams, S.et al. 2012. Potent inhibition of Ca2+-dependent activation of calpain-1 by novel mercaptoacrylates. MedChemComm 3(5), pp. 566-570. (10.1039/c2md00280a) Brasen, J. C., Olsen, L. F. and Hallett, M. B. 2011. Extracellular ATP induces spikes in cytosolic free Ca2+ but not in NADPH oxidase activity in neutrophils. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1813(8), pp. 1446-1452. (10.1016/j.bbamcr.2011.05.002)