Download 8 DJ Begley Short Res CV 4-2013-1

DJ Begley Short CV April 2013
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SHORT RESEARCH CURRICULUM VITAE
DR. DAVID J. BEGLEY
King’s College London,
Blood-Brain Barrier Group
Institute of Pharmaceutical Science
Franklin Wilkins Building
150 Stamford St
London SE1 8WA
UK
Telephone +44(0)20 7848 4327
Fax +44(0)20 7848 4800
Mobile +44(0)7850 403 952
e-mail [email protected]
http://www.kcl.ac.uk/biohealth/research/divisions/ips/research/pharmathera/Staff/Begley.aspx
Education
Nottingham University 1964-1967
B.Sc. Zoology Class II Division 1
Nottingham University 1967-1970
Ph.D. Thesis Title:
“Studies on antibody absorption and transmission in relation to intestinal differentiation in
young rats”
Appointments
1967 - 1970
1971 - 1973
1973 – 1993
1993 to date
Demonstrator in Zoology University of Nottingham
Lecturer in Physiology University of Greenwich
Lecturer in Physiology King’s College London
Senior Lecturer in Physiology King’s College London
Major Research Interests
The mechanisms controlling and limiting the transport of drugs, amino acids and hormones
and other solutes into and out of the central nervous system, across the blood-brain barrier
(BBB) and the blood-cerebrospinal fluid barrier (BCSFB).
In particular:
Structure-activity relationships (SAR) of brain uptake. The physico-chemical factors
determining the uptake, transport and interactions of drugs, peptides, hormones and other
solutes at the blood-brain interfaces. CNS, drug targeting and strategies for enhancing and
optimising the brain uptake of drugs. Locking drugs out of the brain. In vivo and in vitro
studies of the role of passive permeation and specific transport mechanisms in brain uptake. In
vitro models of the BBB and their use as predictors of brain penetration of existing and novel
drugs, and their development as rapid screening methods for combinatorial libraries of
compounds.
SAR of brain efflux mechanisms. The regulation of the internal environment of the brain.
Studies of efflux mechanisms with particular reference to amino acids, peptides hormones and
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drugs. The role of P-glycoprotein, Multidrug Resistance Proteins-MRPs and other efflux
systems, which are directed from brain to blood. The secretion and bulk flow of brain
interstitial fluid and cerebrospinal fluid and the influence of this secretion and flow on the brain
distribution of drugs. Disturbances of BBB function in Lysosomal Storage Diseases (LSDs),
and the challenges of delivering ‘biologicals’ across the BBB in LSDs.
Journal Editorial Board Memberships
Journal of Drug Targeting
Journal of Biomedical Nanotechnology
Expert Opinion on Drug Delivery
Expert Opinion on Therapeutic Targets
International Journal of Neuroprotection and Neuroregeneration
Fluids and Barriers of the CNS
Major Honours
1997-1998 Freiderich Merz-Stiftungsgastprofessur, Johann Wolfgang Goethe-Universitat,
Frankfurt.
1998 to-date Honorary Docent, Institut fur Pharmazeutiche Technologie, Johann Wolfgang
Goethe-Universitat, Frankfurt.
2004/2005 GlaxoSmithKline Sabbatical Research Fellow.
2006/2007 Academic in Residence GlaxoSmithKline
March 2007 Foundation of the European Task Force “Brains for Brain”. A European-based
initiative to promote research leading to the more effective treatment of neuronopathic
lysosomal storage diseases. Brains for Brain was registered as a legal charitable foundation in
2008 and has received funding of 700,000€ to date. (Together with Maurizio Scarpa,
University of Padua, Italy). www.brains4brain.eu, [email protected]
Professional Societies
Fellow of the Zoological Society of London
Member of the Physiological Society
Fellow of the Royal Society of Medicine
Member of the Harveian Society of London
Recent Grants
Marie Curie International Network Grant. FP7 People-2013 ITN “PathChooser”
Innovative, mechanistic-based strategies for delivery of therapeutic macromolecules across
cellular and biological barriers 608373. Net award 3.036M€, value to Kings £237,354.
Engineering and Physical Science Research Council (EPSRC) Technologies for the
Treatment of Brain Disease £332,414 to KCL. (Part of a joint grant with The London School of
Pharmacy, University of Exeter and GSK, Total value ~ £1.7M)
UK MPS Society 2007-2010 The involvement of the BBB in MPS IIIA and MPS IIIB
(Sanfilippo Syndrome) £332,868 Principal applicant
Spanish MPS Society 2007-2009 The involvement of the BBB in MPS IIIA and MPS IIIB
(Sanfilippo Syndrome) Equipment £6,207 Principal applicant
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Actelion Ltd 2008 Transport of Zavesca at the BBB £61,000 Principal applicant
Recent Publications
Pontikis CC, Davidson CD, Steven U. Walkley SU,. Platt F, Begley DJ. (2013) Cyclodextrin
alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable
blood-brain barrier permeability. Journal of Inherited Metabolic Disease. DOI 10.1007/s10545-0129583-x
Muldoon LL. Alvarez JI. Begley DJ. Boado RJ. Del Zoppo GJ. Doolittle ND. Engelhardt B.
Hallenbeck JM. Lonser RR. Ohlfest JR. Prat A. Smeyne RJ. Drewes LR. Neuwelt EA. (2012)
Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow
Metab Doi: 10.1038/jcbfm.2012.153
BegleyDJ,Scarpa M. 2012. Central Nervous System Aspects, Neurodegeneration and the
Blood-Brain Barrier. In, Lysosomal Storage Diseases a Practical Guide. Eds Mehta A and
Winchester B. John Wiley and Sons. pp 166-173
Begley DJ. (2012) Brain Superhighways. Sci Trans Med 4(147): 147fs29. Doi:
10.1126/scitransmed.3004611
Moger J, Garrett,NL, Begley D, Mihoreanu L, Lalatsa A, Lozano M-V, Mazza M. Andreas Schatzlein
A, and Ijeoma Uchegbu I. (2012) Imaging cortical vasculature with stimulated Raman scattering and
two-photon photothermal lensing microscopy J. Raman Spectrosc. 2012, 43, 668–674
Garrett NL,Lalatsa A Begley D, Mihoreanu L,. Uchegbu IF, Schätzlein AG, Moger J. (2012)
Label-free imaging of polymeric nanomedicines using coherent anti-stokes Raman scattering
Microscopy J. Raman Spectrosc. 43, 681–688
Watson CP, Dogruel M, Mihoreanu L, Begley DJ, Weksler BB, Couraud PO, Romero IA, Thomas SA.
(2011) The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human
blood-brain barrier: evidence for involvement of breast cancer resistance protein. Brain Res. Feb
3;1436:111-21.
Wohlfart S, Khalansky AS, Gelperina S, Begley D, Kreuter J. (2011) Kinetics of transport of
doxorubicin bound to nanoparticles across the blood-brain barrier. J Control Release. 154:103-7.
Scarpa M, Ceci A, Tomarin R, Mincarone P, Begley D. (2011) Peronalised medicine in paediatrics:
individualizing treatment in children with rare neurological diseases. The EPMA Journal. 2: 231-239.
Zensi A, Begley D, Pontikis C, Legros C, Mihoreanu L, Büchel C, Kreuter J. (2010) Human serum
albumin nanoparticles modified with apolipoprotein A-1 cross the blood-brain barrier and enter the
rodent brain. J Drug Target 18: 842-848
Abbott N J, Patabendige, A A, Dolman D E, Yusof S R, Begley D J. (2010) Structure and Function of
the Blood-Brain Barrier. Neurobiology of Disease. 37: 13-25
Begley DJ. (2009) Transport of Prions (and other) Proteins across the Blood-Brain Barrier. Exp Neurol.
220: 217-218.
Kurakhmaeva K A. Djindjikhashvili I B. Petrov V E. Balabanyan V U. Voronina T A. Trofimov S S.
Kreuter J. Gelperina S. Begley D. Alyautdin R N. (2009) Brain targeting of nerve growth factor using
poly(butyl cyanoacrylate) nanoparticles. J Drug Target. 17: 564-574
Zensi A, Begley D, Pontikis C, Legros C, Mihoreanu L, Wagner S, Büchel C, von Briesen H, Kreuter
J. (2009) Albumin nanoparticles targeted with Apo E enter the CNS by transcystosis and are delivered
to neurones. J Contr Rel. 137: 78-86
Begley DJ, Pontikis CC, Scarpa M. Lysosomal storage diseases and the blood-brain barrier. Current
Pharmaceutical Design 2008; 14: 1295-1312
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Summerfield SG, Read K, Begley DJ, Obradovic T, Hidalgo IJ, Coggon S, Lewis AV, Porter RA,
Jeffrey P. Central nervous system drug disposition: the relationship between in situ brain permeability
and brain free fraction. J Pharmacol Exp Ther. 2007; 322:205-13.
Begley DJ. Structure and function of the blood-brain barrier. In: Enhancement in Drug Delivery, Eds E
Touitou and BW Barry, CRC Press, Boca Raton 2007, pp575-592.
Begley DJ. The significance of the blood-brain barrier for Gaucher Disease and other lysosomal
storage diseases. In: Gaucher Disease, Eds AH Futerman and A Zimran, CRC Press, Boca Raton
2007, pp 397-421.
Ambruosi A, Khalansky AS, Yamamoto H, Gelperina SE, Begley DJ, Kreuter J. Biodistribution of
polysorbate 80-coated doxorubicin-loaded [14C]-poly(butyl cyanoacrylate) nanoparticles after
intravenous administration to glioblastoma-bearing rats. J Drug Target. 2006; 14:97-105.
Begley DJ. P-glycoprotein the prototypical BBB efflux transporter. In: Ed. Taylor E. Efflux in the
Blood-Brain Barrier, 2006. Nova Science Publishers. USA
Nag S. Begley DJ. Blood-Brain Barrier, Exchange of Metabolites and Gases. In Pathology and
Genetics. Cerebrovascular Diseases. Ed. H. Kalimo, 2005. ISN Neuropath Press, Basel. pp 22-29.
Chishty, M, Begley DJ, Abbott NJ and Reichel A. Interaction of nucleoside analogues with nucleoside
transporters in rat brain endothelial cells. J Drug Target 2004; 12: 265-272
Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the
possibilities. Pharmacol Ther 2004; 104: 29-45
Begley DJ. ABC transporters and the blood-brain barrier. Curr Pharm Des 2004; 10: 1295-1312 7.397
Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. Flavonoid permeability across an in
situ model of the blood brain barrier. Free Radic Biol Med 2004; 36: 592-604
Begley DJ. Understanding and circumventing the blood-brain barrier. Acta Paediar Suppl 2003; 443:
83-91
Begley DJ, Brightman, MW. Structural and functional aspects of the blood-brain barrier. Prog Drug
Res 2003; 61: 39-78
Reichel A, Begley DJ, Abbott NJ. An overview if in vitro techniques for blood-brain barier studies.
Methods Mol Med 2003; 89: 307-324
Chishty M, Begley DJ, Abbott NJ, Reichel A. Functional characterisation of nucleoside transport in rat
brain endothelial cells. Neuroreport 2003; 14: 1087-1090
Krämer SD, Schutz YB, Wunderli-Allenspach H, Abbott NJ, Begley DJ. Lipids in blood-brain barrier
models in vitro II: Influence of glial cells on lipid classes and lipid fatty acids. In Vitro Cell Devel
Biol Anim 2002; 38: 566-571
Krämer SD, Hurley JA, Abbott NJ, Begley DJ. Lipids in blood-brain barrier models in vitro I: Thinlayer chronmatography and high-performance chromatography for the analysis of lipid classes and
long-chain polyunsaturated fatty acids. In Vitro Cell Devel Biol Anim 2002; 38: 557-565
Dacevic MP, Tasic JS, Pejanovic VM, Segal MB, Ugliesie-Kilibarda DD, Isakovic AJ, Begley DJ,
Rakic LM, Redzic ZB. The linkage of glucose to tiazofurin decreases in vitro uptake into rat glial
cells. J Drug Target 2002; 10: 633-636
Kreuter J, Ramge P, Petrov V, Hamm S, Gelperina SE, Engelhardt B, Alyautdin R, von Breisen H,
Begley DJ. Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver
drugs to the CNS via specific mechanisms requiring binding of drug to the nanoparticles. Pharm Res
2003; 20: 4409-416
Reichel A, Abbott NJ , Begley DJ. Evaluation of the RBE4 cell line to explore carrier-mediated drug
delivery to the CNS via the L-system amino acid transporter at the blood-brain barrier. J Drug Target
2002; 10: 277-283
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Chishty, M, Reichel A, Begley DJ, Abbott NJ. Glial induction of blood-brain barrier-like L-system
amino acid transporter in the ECV304 cell line. Glia 2002; 39: 99-104
Chishty M, Reichel A, Abbott NJ, Begley DJ. S-adenosylmethionine is substrate for carrier mediated
transport at the blood-brain barrier in vitro. Brain Res 2002; 942: 46-50
Abbott NJ, Khan EU, Rollinson CM, Reichel A, Janigro D, Dombrowski SM, Dobbie MS, Begley DJ.
Drug resistance in epilepsy: the role of the blood brain barrier. Novartis Found Symp 2002; 243: 2847
Chishty M, Reichel A, Siva J, Abbott NJ, Begley DJ. Affinity for the P-glycoprotein efflux pump at the
blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines. J Drug Target
2001; 9: 223-228
Alyautdin RN, Reichel A, Lobenberg R, Ramge P, Kreuter J, Begley DJ. Interaction of
poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro. J Drug Target
2001; 9: 209-221
Habgood MD, Begley DJ, Abbott NJ. Determinants of passive drug entry into the central nervous
system. Cell Mol Neurobiol 2000; 20: 231-253
Reichel A, Begley DJ, Abbott NJ. Carrier-mediated delivery of metabotropic glutamate receptor ligands
to the central nervous system: structural tolerance and potential of the L-system amino acid
transporter at the blood-brain barrier. J Cereb Blood Flow Metab 2000; 20: 168-174
PhD Students Supervised
2005 Evaluation of Blood-Brain Barrier Models for Measurement and Prediction of Brain
Drug Penetration. Kevin Read. GSK, External Student-part time (Second Supervisor)
2005 An Investigation of Blood-Brain Barrier Penetration of the Anticholinesterases
Physostigmine and Pyridostigmine in the Guinea Pig. David Baker (First supervisor)
2004 In situ Permeability and Neuroprotection studies at the Blood-Brain Barrier. Zeeshan
Qaiser. (Second Supervisor)
2004 Effects of P-glycoprotein on the Brain Penetration of Drugs in the CF-1 mdr1a -/Mouse Model. Andrew Pike. Merck, External Student-part time (First Supervisor)
2003 The Role of Pgp at the Blood-Brain Barrier. Ehsan Khan . (Second Supervisior)
2002 Rules Governing Drug Transport into the Brain. Mansoor Chisty. (Second Supervisor)
2001 Lipid Composition and Modulation of Transport Function in an in vitro Model of the
Blood-Brain Barrier. Johannah Hurley. (Second Supervisor)
2000 Characterisation and applications of RBE4 as an in vitro Model of the Blood-Brain
Barrier. Christopher Rollinson. (Second Supervisor)
1990 Linda Squires. A Study of Insulin in Plasma and Cerebrospinal Fluid by High
Performance Liquid Chromatography. (First Supvervisor)
1984 An in vivo and in vitro study of gammaglobulin absorption ans transmission in the rat
small intestine. Stephen Polacarz (First Supervisior)
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PhD Students Examined
2009 Phage Display and Experimental Brain Therapeutics. Matthew Smith. University of
Cardiff
2009 Amyloid Beta Transport and Effects on Permeability in a Human Brain Endothelial
Cell Line. Leon Tai. The Open University
2008 The Brain Distribution of Glucocorticoids and the role of P-Glyocprotein. Brittany
Mason . Kings College London
2005 Studies on the Roles of Endocytic Pathways in Drug Delivery and Resistance in
Leukaemia cells. Saly Al-Taei. University of Cardiff
2004 The transport and distribution of thyroxine (T4) from the cerebrospinal fluid into brain.
Nouhad Kassem. Kings College London
2001 Interaction between Intestinal Metabolic and Secretory Efflux Systems. Lauretta Chan
University of Newcastle upon Tyne
2001 In vitro Transport of Peptides Across Lung Epithelial Cell Monolayers and Correlation
with in vivo Absorption. Balvinder Singh Matharu. Kings College London
2000 In-Vitro Blood-Brain Barrier Characteristics: Interplay between its Physiology,
Pharmacology and Pathophysiology. Peter Gaillard. University of Leiden. The Netherlands.
1999 Pathophysiology of Blood-Brain Barrier, Brain Edema and Cell injury Following
Hyperthermia: New Role of Heat Shock Protein, Nitric Oxide and Carbon Monoxide. Hari
Shankar Sharma. University of Uppsala, Sweden.
1997 The Mechanism by which Hyperammonaemia may cause Hepatic Encephalopathy.
Kevin Smart. UMDS, St. Thomas’, University of London.
1996 Devlopmental Changes in Acid Amino Acid Entry into Brain , CSF and Choroid Plexus
of the Rat. Hameed Al-Sarraf. UMDS, St. Thomas’, University of London.
1994 Zinc and Manganese Homeostasis in Brain. Paul Franklin. Unversity of Sunderland.
Post-Doctoral Fellows
2009 Dr Svetlana Drndarski (UK) Currently in post KCL.
2007 Dr. Larisa Mihoreanu (Romania)
2007 Dr. Celine Legros (France)
2006 Dr. Charles Pontikis (UK)
1993 Prof. Renard Alyautdin ( Russia) Presently Professor of Pharmacology and Dean for
External students, Sechnov Medical Academy, Moscow.
1992-1993 Dr. Andreas Reichel (Germany) Presently Head DMPK Schering/Plough, Berlin.
1999-2000 Dr. Stefanie Krämer (Switzerland) Presently Professor Pharmacy, ETH, Zurich.
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1991 Dr. Anton Vladić (Croatia) Presently Professor Zagreb School of Medicine.
1982-1984 Dr. Berislav Zloković (Serbia) Presently Professor of Neurosurgery, Rochester
NY.
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