Department of Pharmacy and Pharmacology

amanda_mackenzie

Senior Lecturer

5 West 2.45

Email:

Tel: +44 (0) 1225 385796 

 

Dr Amanda Mackenzie  

Profile

My research areas range from inflammation, cell biology and the biophysical properties of ion channels.

ATP-gated P2X receptors

Extracellular adenosine 5'-triphosphate (ATP) is an established intercellular signalling molecule in the immune system acting at two classes of receptor: metabotropic G protein coupled P2Y receptors and ionotropic P2X receptors. P2X receptors (P2X1-P2X7) can function as homomeric or heteromeric subunit assemblies forming a non-selective cation channel. Each P2X receptor subtype can be distinguished by distinct pharmacological or biophysical properties with a range of permeabilities to calcium. P2X7 receptors are predominately expressed by cells of the immune system, including monocytes, macrophages and lymphocytes. The P2X7 receptor is uniquely characterized by a decreased sensitivity to extracellular ATP compared with other P2X receptors and rapid coupling to a membrane 'pore' that transports large molecular weight dyes.

Cell biology of immune cells

My research group is interested in the functional role of ion channels, particularly P2X receptors, in the innate immune response to pathogen-derived molecules. In particular, we are interested in the molecular signalling pathways underlying the production of the inflammatory cytokine interleukin 1 (IL-1Beta). The production of bioactive IL-1Beta is a tightly controlled multi-step process: first IL-1Beta is produced as an inactivate precursor 31 kD pro-IL-1Beta, this is cleaved to produce bioactive 17 kD IL-1Beta and then finally the bioactive IL-1Beta is rapidly secreted from the macrophage. The processing and cleavage of the IL-1Beta precursor is achieved by a protease called caspase-1 that is activated within a multi-protein complex termed the NLRP3 inflammasome. We have specific interest in the pathways leading to activation of the NLRP3 inflammasome activation and the secretion of inflammatory cytokines.

The P2X7 Interactome (with Dr M. Young, Cardiff University)

This is a collaborative initiative to identify proteins that interact with P2X7 receptors expressed by inflammatory cells to form the P2X7 receptor interactome. Further details can be found at www.P2X7.co.uk.

Other research interests include vascular inflammation and ion channels expressed by non-excitable cells.

Co-founded a spin out company Glythera with Dr A. Watts (University of Bath) (www.glythera.com).
 

Our research is funded by the Medical Research Council, University of Bath and BBSRC.

 

 

 

Publications

Wickens, R. A., Ver Donck, L., Mackenzie, A. B. and Bailey, S. J., 2017. Repeated daily administration of increasing doses of lipopolysaccharide provides a model of sustained inflammation-induced depressive-like behaviour in mice that is independent of the NLRP3 inflammasome. Behavioural Brain Research

Stokes, L., MacKenzie, A. B. and Sluyter, R., 2016. Editorial:roles of ion channels in immune cells. Frontiers in Immunology, 7, 48.

Jackson, M., Wickens, R., Bailey, S. and Mackenzie, A., 2016. The profile of P2X7 receptor expression and properties in polarized primary mouse microglia cultures. Journal of Psychopharmacology, 30 (Abstract Supplement ), A98.

Wickens, R., Ver Donck, L., Mackenzie, A. and Bailey, S., 2015. The effect of housing conditions on lipopolysaccharide-induced depressive-like behaviour in mice. Journal of Psychopharmacology, 29 (8 (Abstract Suppleme), A08.

Wickens, R., Ver Donck, L., Bailey, S. and Mackenzie, A., 2015. Primary microglia isolated from neonatal mice provide a model for the study of NLRP3 inflammasome and the effect of long-term hypoxia. In: Society for Neuroscience 2015, 2015-10-17 - 2015-10-21, Chicago.

Wickens, R., Ver Donck, L., Mackenzie, A. and Bailey, S. J., 2014. Acute And Chronic Lipopolysaccharide Induces Sickness But Fails To Produce A Depressive-Like Behaviour In Mice. Journal of Psychopharmacology, 28 (8), A107.

Foster, J. G., Carter, E., Kilty, I., Mackenzie, A. B. and Ward, S. G., 2013. Mitochondrial superoxide generation enhances P2X7R-mediated loss of cell surface CD62L on naïve human CD4+ T lymphocytes. The Journal of Immunology, 190 (4), pp. 1551-1559.

Wickens, R. A., Ver Donck, L., Bailey, S. J. and Mackenzie, A. B., 2013. Lipopolysaccharide regulation of the NLRP3 inflammasome and proIL-1β under normoxic versus hypoxic conditions in cultured (BV-2) mouse microglia. Proceedings of the British Pharmacological Society, 11 (3).

Watts, Andrew, 2012. Materials and methods relating to glycosylation. A61K47/48- EP2442831 (A2), 25 April 2012.

Thompson, B. A. N., Storm, M. P., Hewinson, J., Hogg, S., Welham, M. J. and Mackenzie, A. B., 2012. A novel role for P2X7 receptor signalling in the survival of mouse embryonic stem cells. Cellular Signalling, 24 (3), pp. 770-778.

Watts, Andrew, 2012. Functionalising reagents and their uses. CN102317305 (A), 11 January 2012.

Watts, Andrew, 2011. Thiol-Functionalising Reagents and Their Uses. C07K1/13- EP2373675 (A2), 12 October 2011.

Watts, Andrew, 2010. Materials and Methods Relating to Glycosylation. A61K47/48- CA2768155 (A1), 23 December 2010.

El Ouaaliti, M., Moore, S. F. and Mackenzie, A. B., 2010. The role of protein kinase C and phosphoinositide 3-kinase in P2X7 receptor-mediated oxidation and IL-1beta processing. Purinergic Signalling, 6 (1), p. 49.

Mackenzie, A., Welham, M. and Thompson, B., 2010. Expression of ATP-gated P2X7 receptors in mouse embryonic stem cells. Purinergic Signalling, 6 (Supplement 1), p. 129.

Moore, S. F. and Mackenzie, A. B., 2009. NADPH oxidase NOX2 mediates rapid vellular oxidation following ATP stimulation of endotoxin-primed macrophages. The Journal of Immunology, 183 (5), pp. 3302-3308.

Mackenzie, Amanda, 2009. Detection and Functionalisation of S-Nitrosylated Polypeptides. G01N33/68- WO2009024791 (A1), 26 February 2009.

Moore, S. F. and Mackenzie, A. B., 2008. Species and agonist dependent zinc modulation of endogenous and recombinant ATP-gated P2X7 receptors. Biochemical Pharmacology, 76 (12), pp. 1740-1747.

Hewinson, J., Moore, S. F., Glover, C., Watts, A. and Mackenzie, A. B., 2008. A key role for redox signaling in rapid P2X7 receptor-induced IL-1 β processing in human monocytes. The Journal of Immunology, 180 (12), pp. 8410-8420.

This list was generated on Fri Oct 20 11:22:59 2017 IST.

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