Department of Pharmacy and Pharmacology

amanda_mackenzie

Senior Lecturer

7W 3.10

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Tel: +44 (0) 1225 385796 

 

Dr Amanda Mackenzie  

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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

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