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Professor Oliver Dolly at SFI's Translational Medicine 2010 symposium
27 October 2010
Professor Oliver Dolly, SFI Research Professor and Director of the International Centre for Neurotherapeutics (ICNT) at Dublin City University presented the findings of his research at the recent 'Translational Medicine 2010' symposium and live webinar organised by the SFI at the Science Gallery, in Dublin.
The abstract of Professor Dolly's talk is below.
Professor Dolly is a world leader in molecular neurobiology who has performed pioneering investigations that have helped decipher a molecular basis for neuronal communication, especially in identifying and structurally characterising SNARE ( an acronym derived from “SNAP (Soluble NSF Attachment Protein) REceptors”) proteins which are responsible for the quantal release of transmitters. He is also widely acknowledged as having conducted some of the seminal research on Botulinum neurotoxins.
He graduated from NUI Galway with BSc and MSc degrees and with a PhD from the University of Wales at Cardiff. After positions at the State University of New York and University of Maryland, he was recruited by Imperial College London.Over almost thirty years at Imperial, he acquired a worldwide reputation for his work on molecular neurobiology.
The importance of his papers is reflected by his numerous citations and invited lectures at premier international conferences. He was promoted to a Professorship position at Imperial in 1989 and was awarded a DSc by the University of London in 2002. He returned to Ireland in 2003 as a Science Foundation Ireland Research Professor and established the International Centre for Neurotherapeutics at Dublin City University. Prof. Dolly has 263 publications including 179 refereed full papers with papers in Nature, PNAS and many leading journals. He has edited 4 books, contributed 50 book chapters and reviews and given many conference presentations. His world class status as an extremely creative/industrious researcher is obviated by the patents he has secured and over 7800 citations. These and other applaudable achievements in Ireland have been recognised by the award of the Conway Research Medal by the Royal Academy of Medicine Ireland, President of DCU Award for Research and election as a member of the Royal Irish Academy.
Abstract
Novel bio-therapeutics to normalise neuronal transmission.
J. Oliver Dolly, M.Sc., Ph.D., D.Sc. (Lond.), MRIA,
SFI Research Professor,
Director, International Centre for Neurotherapeutics,
Dublin City University, Glasnevin, Dublin 9.
E-mail:oliver.dolly@dcu.ie
Functioning of the nervous system requires a fine balance and co-ordination between excitatory and inhibitory signals, but such precise control can be lost in several diseases. Our multi-disciplinary research is focussed on devising neurotherapeutics with selective abilities to ameliorate the symptoms of defects arising from abnormal hypo- or hyper-excitability of peripheral nerves and the consequential under- or over-exocytosis of transmitters.
Debilitating disorders (e.g. multiple sclerosis, MS) can cause muscle weakness due to compromised propagation of signals along nerve axons and associated reduction in synaptic transmission, apparently, due to hyper-polarising K^+ currents that appear after MS-induced demyelination. Our observation of an unique oligomeric subtype of voltage-sensitive K^+ channel (Kv1) in autopsies from MS patients has validated the search for an exclusive blocker of the disease-associated channel to overcome that detrimental effect. This promising and worthwhile task is being aided by a cassette cloning technology recently developed here which has allowed recombinant creation of Kv1 channels in mammalian cultured cells^1 , that mimic their counterparts in normal and diseased states. These K^+ channels are yielding insight into the structural details of the equivalent proteins 'in situ', and serving as ‘authentic’ targets for screening specific inhibitors using the automated robotic platforms established.
In a huge group of other conditions (e.g. defects or damage to the brain/spinal cord), abnormal release of acetylcholine is being attenuated with astounding success worldwide by localised injections of type A botulinum neurotoxin (BoNT) into the affected muscles. Although most of this biotherapeutic in clinical use was isolated from 'Clostridium botulinum', several serotypes have since been produced recombinantly in 'E.coli' as single-chains, affinity purified and activated only when needed*2 . Using this advantageous strategy, we have engineered several new variants of BoNT-based therapeutics whose pharmacological properties are tailored for different research or potential clinical applications. In particular, long-acting, novel generations capable of inhibiting the release of pain mediators from sensory neurons*3 have been generated, with a view to extending the usefulness of BoNT to treat inflammatory*4 and neuropathic forms of chronic pain.
*1 Al-Sabi, A., Shamotienko, O., Ní Dhochartaigh, S., Muniyapppa, N., LeBerre , M., Shaban, H., Wang, J., Saak, J., and Dolly, J.O. Arrangement of Kv1 asubunits dictates sensitivity to tetraethylammonium, J. Gen. Physiol. 2010, _136_: 273-282.
*2 Wang, J., Meng, J., Lawrence, G. W., Zurawski, T. H., Sasse, A., Bodeker, M. O., Gilmore, M. A., Fernandez-Salas, E., Francis, J., Steward, L. E., Aoki, K. R. and Dolly, J. O. Novel chimeras of botulinum neurotoxin A and E unveil contributions from the binding, translocation and protease domains to their functional characteristics, J Biol Chem. '2008,' _283_:16993-17002
*3 Meng, J., Ovsepian, S. V., Wang, J., Pickering, M., Sasse, A., Aoki, K. R., Lawrence, G. W. and Dolly, J. O. TRPV1-mediated CGRP release excites sensory neurons and is attenuated by a novel toxin with anti-nociceptive potential, J Neurosci. 2009,'_29_:4981-4992
*4 Wang, J., Zurawski, T., Meng, J., Wheeler, L. and Dolly, J.O. A di-leucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic, J Biol Chem. (under review)
This research is financed by a Science Foundation Ireland PI grant, an award from the Irish Higher Education Authority (PRTLI 4 for Target-driven therapeutics and theranostics) and ongoing support from Allergan Inc. for basic research.