Wann, Kenneth - Cardiff University - School of Pharmacy and Pharmaceutical Sciences

个人简介

I graduated in Physiology from Aberdeen University and remained there to establish an electrophysiology laboratory as a PhD student. I was appointed to a lectureship in 1972. I then moved to the Welcome Foundation Laboratories in Beckenham where I was employed as a senior scientist / electrophysiologist from 1982-1986. In July 1986 I returned as a Reader to Academia to the MRC Clinical Research centre in Northwick Park, London. Whilst based in the division of Anaesthesia there I revisited a former interest of mine - that of high pressure studies. I had a short spell in the James Black Foundation in London in 1990-1991 before moving to the Department of Physiology in the Royal Free Hospital Medical School (now the Royal Free and University College Medical School). I took up my present post as a cellular Physiologist / Pharmacologist in the School of Pharmacy in Cardiff University in 1996. I have acted as consultant to many of the major Pharmaceutical Companies including Pfizer, Roche, Wellcome, Johnson and Johnson, Pharmacia, Upjohn, Wyeth and the James Black Foundation. My specific scientific interests include membrane potassium channels, cardiac arrhythmias, cell death, bacterial signalling, neurodegenerative diseases and epilepsy. I have specific knowledge of ion channel-targeted drugs and have first hand experience of drug design programmes in areas such as epilepsy, stroke, cardiac arrhythmia and parasitic diseases and pesticides. Current work focuses on the role of ion channels in disease and bacterial signalling. I have previously served on several Research Council Committees, have served as an MRC Advisory Board member and on the UK Medical Research Council College of Experts for the Physiological Systems and Clinical Sciences panel.

研究领域

Characterisation of ion channels in non excitable cells Role of ion channels in cell proliferation and cell death Bacterial ion channels and signalling Bioluminescent indicators Ion channels and disease Non-excitable cells, like excitable cells, possess plasma membrane ion channels. Evidence has slowly accumulated that these channels have surprisingly key roles to play in the life and death decisions a cell may make. Our work attempts to define the role of plasma membrane ion channels in cellular processes such as proliferation, apoptosis and differentiation in robust cell models. To this end we use a combination of single cell patch-clamp electrophysiology, reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR (Q-PCR) and functional assays of cell growth and viability. Proliferation assays (e.g. using commercially available MTS kits, and direct cell counting), apoptosis assays (e.g. using Annexin-V and propidium iodide labelling, and TUNEL labelling) and functional assays (e.g. mineralisation of osteoblast-like cells as assessed by Alizarin red staining) are used to delineate effects. Much of the work uses established cell lines, including osteosarcoma-derived cells such as osteoblast-like MG63 and SaOS2 cells, breast cancer (MCF-7), prostate cancer (LNCaP) cells, human brain astrocytoma (MOG-G-UVW), neuroblastoma (SH-SY5Y) and pluripotent embryonal carcinoma (NTERA-2). In neuronal cell lines, we have focused on plasma membrane K+ channels and channels in subcellular organelles such as the endoplasmic reticulum (e.g. ryanodine receptor) and mitochondria. Understanding the links between modified channel function and activation of the cell death pathway remains the prime focus. Methods such as patch-clamp electrophysiology, planar bilayer work, RT-PCR and apoptotic assays are utilised. Cell lines (e.g. SH-SY5Y, MOG-G-UVW, NTERA-2) and primary cells are used. The results of this work will hopefully both add to our understanding of the role of ion channels in fundamental cellular processes, and have relevance for diseases such as the degenerative illnesses (e.g. osteoporosis, neurodegeneration) and the cancers. The long term goal is to identify possible ion channel targets for therapeutic intervention in various diseases, including debilitating central nervous system disorders such as Alzheimer's disease. Ionic signalling in Bacteria Ca2+ is king of the messengers in eukaryotic cells and there is indirect evidence that Ca2+ plays a key role in shaping physiological processes in prokaryotes. These include tumbling and chemotaxis, the cell cycle, spore formation, virulence and pathogenesis, competence, and the regulation of protein synthesis. Clear definitive evidence has been lacking because of a lack of correlation of cytosolic free Ca2+ with bacterial growth and gene expression, and the lack of good candidates for a Ca2+ channel. The aim of this work is to show definitively that cytosolic free Ca2+ is a signal in bacteria controlling cell shape, growth and gene expression. One mechanism by which we are trying to do this is by bringing together electrophysiological and bioluminescent techniques in order to identify novel mechanisms for calcium influx/efflux. Current work involves the extensively studied bacterial mechanosensitive channels (MscS and MscL) and uses Ca2+ as signal for mechanosensitive channel opening to screen for lead compounds that could be employed as antimicrobials. Bacterial metabolic 'toxins' in diabetes Bacteria in the gut, and in other hypoxic environments, produce hydrogen and methane, and small organic molecules when they metabolise carbohydrates such as lactose. The aim of this new work is to test the hypothesis that small organic toxins produced by anaerobic bacteria in the gut cause/contribute to diabetes and other major diseases. The strategy is to use a culture of pancreatic β -cells, already transformed with firefly luciferase and transfected with the photoprotein aequorin, enabling changes in cytosolic free Ca2+ and K+ channel conductance to be correlated with insulin secretion and cell growth. Bioluminescent indicators The measurement of the free Ca2+ inside cells has been the key to our understanding many aspects of intracellular signalling which underpin cellular processes as diverse as fertilization, secretion, contraction and movement, excitability and growth. Bioluminescence is one of the methods routinely used by cell biologists to measure free Ca2+ inside cells and in particular aequorin a photoprotein which emits light as a response to changes in physiological Ca2+. The goals of this project have been to devise a construct that would detect intracellular Ca2+ and also serve as a probe of ion channel function. Using genetic engineering techniques, we have constructed a fusion protein between β2 (a modulatory subunit of the MaxiK channel) and aequorin. This construct does in principle monitor levels of [Ca2+]i close to ion channel microdomains and, provide information about the way the channel assembles and, if fully functional, will also indicate how the assembled channel responds to changes in local [Ca2+]i. This recombinant protein will enable us to examine channel modulation and expression from a new perspective. Origin of coelenterate bioluminescence The aims of this research are first to establish which luminous marine species are present in Pembrokeshire. The goals are then to determine the biosynthetic pathway for coelenterazine in Obelia and to investigate how the kinetics of Obelia's flash are controlled by investigating calcium regulation within the photocyte. The long term objective is to develop Obelia as a model system to study new drugs which work on potassium and calcium ion channels.

近期论文

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Abdulkareem, Z.et al. 2016. Knockdown of the small conductance Ca2+-activated K+ channels is potently cytotoxic in breast cancer cell lines. British Journal of Pharmacology 173(1), pp. 177-190. (10.1111/bph.13357) pdf Cox, C., Wann, K. T. and Martinac, B. 2014. Selectivity mechanisms in MscS-like channels: From structure to function. Channels 8(1), pp. 5-12. (10.4161/chan.27107) pdf Burley, D.et al. 2014. Natriuretic peptides modulate ATP-sensitive K+ channels in rat ventricular cardiomyocytes. Basic Research in Cardiology 109(2), article number: 402. (10.1007/s00395-014-0402-4) pdf Cox, C.et al. 2013. Selectivity mechanism of the mechanosensitive channel MscS revealed by probing channel subconducting states. Nature Communications 4(7), article number: 2137. (10.1038/ncomms3137) Vassel, N.et al. 2012. Enzymatic activity of albumin shown by coelenterazine chemiluminescence. Luminescence 27(3), pp. 234-241. (10.1002/bio.2357) Campbell, A.et al. 2010. Bacterial metabolic 'toxins': A new mechanism for lactose and food intolerance, and irritable bowel syndrome. Toxicology 278(3), pp. 268-276. (10.1016/j.tox.2010.09.001) Henney, N.et al. 2009. A large-conductance (BK) potassium channel subtype affects both growth and mineralization of human osteoblasts. American Journal of Physiology - Cell Physiology 297(6), pp. C1397-C1408. (10.1152/ajpcell.00311.2009) Naseem, R.et al. 2009. ATP regulates calcium efflux and growth in E. coli. Journal of Molecular Biology 391(1), pp. 42-56. (10.1016/j.jmb.2009.05.064) Naseem, R.et al. 2008. pH and monovalent cations regulate cytosolic free Ca2+ in E. coli. BBA - Biochimica et Biophysica Acta 1778(6), pp. 1415-1422. (10.1016/j.bbamem.2008.02.006) Burley, D.et al. 2008. Evidence for serca and BKCa activation in BNP protection of reperfused myocardium [Abstract]. Journal of Molecular and Cellular Cardiology 44(4), pp. 717. (10.1016/j.yjmcc.2008.02.015) Coles, B.et al. 2008. Potassium channels in hippocampal neurones are absent in a transgenic but not in a chemical model of Alzheimer's disease. Brain Research 1190, pp. 1-14. (10.1016/j.brainres.2007.10.071) Li, B.et al. 2007. BK channels in human osteoblast-like cells - Properties and function [Abstract]. Journal of Bone and Mineral Research (JBMR) 22(S1), pp. S161., article number: M144. (10.1002/jbmr.5650221405)