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The Neuroprotective Effect of the Heat Shock Proteins

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The Neuroprotective Effect of the Heat Shock Proteins THE NEUROPROTECTIVE EFFECT OF THE HEAT SHOCK PROTEINS MARCUS JAMES DERMOT WAGSTAFF A thesis submitted to the University of London for the degree of Doctor of Philosophy. October 1997. Department of Molecular Pathology Windeyer Institute of Medical Sciences Division of Pathology University College London Medical School London ProQuest Number: 10105625 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10105625 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The work presented in this thesis investigates the protective effects of the heat shock proteins in neurons against the cytopathic effects of exogenous stress. The heat shock proteins (hsps) are a group of proteins that are overexpressed in cells in response to temperatures above the cells optimum growth tenq)erature. Cerebral ischaemia in vivo increases the levels of heat shock proteins and their mRNAs. A brief ‘sub-lethal’ ischaemic insult prior to a ‘lethal’ ischaemic stress has two effects. Firstly, hsps are overexpressed, and secondly, the extent of neuronal damage is significantly reduced as con^ared with models that undergo the single ‘lethal’ ischaemic insult. The work in this thesis investigates whether overexpression of hsps is protective against ischaemia in neurons. Initially, the levels of a range of hsp mRNA and protein overexpression are characterised over time during a focal cerebral ischaemic insult in the core region of ischaemia in rats in vivo, achieved by middle cerebral artery occlusion (MCAQ). This thesis proceeds to describe the design, construction and characterisation of recombinant HSV-1 vectors that, after delivery, significantly overexpress hsps in a neuron-derived cell line. These vectors were created with the ultimate goal of heat shock gene delivery to the rat brain in vivo. The protective effect of hsp overexpression was subsequently assessed in neurons in response to heat shock, ischaemic stress and ap opto sis. The heat shock transcription factor, HSFl, stimulates the transcription of the heat shock genes in response to stress. Using a constitutively active deletion mutant of HSFl, this thesis profiles the expression of the hsps in response to recombinant HSV-1 vector mediated delivery and overexpression of the H-BH gene in neuronal cells, and also characterises the protective effects of overexpression of the mutant in similar conditions as described above. Acknowledgements I would like to thank Professor David S. Latchman for all his support, ideas and words of encouragement throughout the duration of the project. I would also like to thank Dr. Robert S. CoflSn for his constant guidance and patience. Professor Jacqueline de BeUeroche and Dr. Yolanda Collaço-Moraes deserve a special mention for all their help and teaching with the mRNA work and Dr. M. Keith Howard for his technical advice concerning cell lines, viruses, and a whole host of other matters. I must also thank the other members of the Medical Molecular Biology Unit, in particular Dr. Suzanne Thomas, Dr. Lynn Rose, Dr. Anastasis Stephanou and Mr. John Estridge, not only for their advice, but also for their friendship and tireless support. I am very grateful to the Dean of University College London Medical School, Prof John R Pattison, and also to Prof. Anthony Segal and Mr. Tom Wale without whose support this project would have been impossible, and to PhiHp Taylor whose friendship and bottomless pot of coffee has just about kept me sane. Finally, I would like to thank my parents for reasons far beyond those which can be put on paper. This work was supported by a scholarship from the Sir Jules Thom Charitable Tmst made available through University College London Medical School. Declaration AH the work presented in this thesis is the work of Marcus Wagstaff. Contributions by other researchers to the work presented is acknowledged below: 1) Mr. Benjamin S. Aspey, at the Reta Lila Weston Institute of Neurological Studies, University College London carried out the middle cerebral artery occlusion work. 2) The brain tissue mRNA extraction in Chapter Three was carried out by Dr. Yolanda Collaço-Moraes and Professor Jacqueline de BeUeroche at the department of Biochemistry, Charing Cross Hospital Medical School, London. 3) Rat dorsal root ganghon ceUs were dissected and initiaUy cultured by Ms. Elizabeth Ensor at the department of Molecular Pathology, University CoUege London Medical School. Abbreviations Ab Antibody APS Ammonium persulphate ATP/ADP/AMP Adeno sine tripho sphate/dipho sphate/monopho sphate bp Base pairs BDNF Brain derived neurotrophic factor BiP Immunoglobulin heavy chain binding protein BGH Bovine growth hormone BHK Baby hamster kidney BSA Bovine serum albumin cAMP N6,2’-0-Dibutyryladenosine3 ’ : 5 ’-cychc monophosphate CAT Chloramphenicol acetyl transferase cDNA Conq)lementary DNA CMC Carboxymethyl cellulose CMV Cytomegalovirus CNS Central nervous system CPE Cytopathic ejffect cpm Counts per minute ddHzO Double distilled water DEPC Diethyl pyro carbonate DHFR Dihydrofolate reductase DMEM Dulbecco’s modified Eagle’s medium DMSO Dimethylsulfoxide DNA Deoxyribonucleic acid DRG Dorsal root ganghon E Early (gene) ECL Enhanced chemiluminescence EDTA Diaminoethanetetra-acetic acid, disodium salt EMCV Encephalomyocarditis virus ER Endoplasmic reticulum ECS Foetal calf serum FGM Full growth medium FKBP FK506 binding protein GABA Gamma aminobutyric acid GFAP Glial-fibrillary acidic protein GFP Green fluorescent protein GR Glucocorticoid receptor HBSS Hank’s balanced salt solution HCF Host cell factor Hepes N- [2-hydroxyethyl] pip erazine-N ’ - [2- ethanesulfonic acid] HMBA Hexamethylene bisacetamide HO-1 Haem oxygenase-1 HSC Heat shock cognate HSE Heat shock element HSF Heat shock factor HSP Heat shock protein HSV Herpes Sinqplex Virus HSV-1 Herpes Simplex Virus type 1 ICP Infected cell protein IE Immediate-early (gene) 1RES Internal ribosome entry site IRE Internal repeat long 1RS Internal repeat short kb Kilobase kDa KiloDalton L Late (gene) LAX Latency associated transcript LB Luria Bertani medium L I5 Medium Liebowitz’s 15 medium LMP Agarose Low melting point agarose LTR Long terminal repeat LZ Leucine zipper MAP Mitogen-activated protein MAP2 Microtubule associated protein 2 MWt Molecular weight MCA(0) Middle cerebral artery (occlusion) MOI Multiplicity of infection MoMLV Moloney murine leukaemia virus MR Mineralocorticoid receptor NGF Nerve growth factor NMDA N-methyl-D- asp artate NO(S) Nitric oxide (synthase) OR Oestrogen receptor PAGE Polyacrylamide gel electrophoresis PDF Pre-sequence binding factor PBS Phosphate buffered saline pfli Plaque-forming units PPIase Peptidyl prolyl cis-trans isomerase PR Progesterone receptor RM Rainbow marker RNA Ribonucleic acid mRNA Messenger RNA rpm Revolutions per minute SDS Sodium dodecyl sulphate SEM Standard error of the mean SFM Serum jfree medium SRP Signal recognition particle SSC Standard saline citrate SV40 Simian virus 40 TAE Tris- acetate-EDTA buffer TBP TATA binding protein TCP t-corüplex polypeptide TdT Terminal deoxynucleotidyl transferase TEMED N,N,N’ ,N ’ - tetramethyl- ethylenediamine TRiC TCP-1 ring complex TRL Termmal repeat long TRS Terminal repeat short TTC 2,3,5-triphenyltetrazoUum chloride TUNEL TdT-mediated dUTP nick-end labelUng Tween 20 Polyoxy ethylene- sorbitan monolaurate UCLMS University CoUege London Medical School UL Unique long US Unique short UV Ultraviolet VSCC Voltage-sensitive calcium channels Publications 1) Wagstaff Collaço-Moraes Y., Aspey B.S., CoflSn R.S., Harrison T .at cil man D.S., de BeUeroche J.S. (1996) Focal cerebral ischaemia increases the levels of several classes of heat shock proteins and their corresponding mRNAs. In Press. Mol. Brain. Res. 42 (2), 236-244. 2) CoflSn R.S., Thomas S.K., Thomas N.S.B., LUley C.E., Pizzey A.R., Griffiths C.H., Gibb B.J., Wagstaff M.J.D., Inges S.J., Binks M.H., Chain B.M., Thrasher A T, Rutault K., Latchman D.S. (1997) Pure populations of transduced primary human ceUs can be produced using GFP expressing herpes virus vectors and flow cytometry. Submitted to Gene Therapy. CONTENTS Abstract 2 Acknowledgements 3 Declaration 3 Abbreviations 4 Publications 7 Index of Figures 15 Index of Tables 18 CHAPTER 1 - INTRODUCTION 19 1.0 Introduction 20 1.1 The Biology of the Heat Shock Proteins 20 1.1.1 Overview 20 1.1.2 The Heat Shock Protein 70 Family 24 1.1.3 The Heat Shock Protein 60 Family 31 1.1.4 The Heat Shock Protein 90 Family and the Untransformed Steroid Receptor Complex 36 1.1.5 Hsp 5 6 and the Peptidyl Prolyl Isomerases 3 8 1.1.6 Heat Shock Protein 27 39 1.1.7 Heat Shock Protein 32 41 1.1.8 Other Heat Shock Proteins 41 1.1.9 The Role of the Heat Shock Proteins in Cell Stress 43 1.1.10 The Heat Shock Transcription Factors and HSP Gene Regulation 46 1.2 Cerebral Ischaemia 53 1.2.1 Introduction 53 1.2.2 The Appearance and Pathogenesis of Cell Death During Severe Cerebral Ischaemia. 53 1.2.3 Changes in Gene Expression During Cerebral Ischaemia 57 1.2.4 Heat Shock Protein Expression in Cerebral Ischaemia
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