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'Towards a Mouse Modec Fo R Maemopfiicia ‘Towards A Mouse ModeC fo r MaemopfiiCia tRaecfiet Kenny I'Haemostasis ‘R&searcfi Qroup, CtinicaC ‘R&searcfi Centre, Marrow. Submitted fo r the degree o f TfdD. 1992 1 ProQuest Number: 10609858 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 com plete 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 10609858 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ABSTRACT OF THESIS TOWARDS A MOUSE MODEL FOR HAEMOPHILIA Haemophilias A and B are X-linked recessive bleeding disorders caused by deficiencies of coagulation factors VIII and IX respectively. Present treatment for the disease, by replacement therapy with products extracted from large volumes of pooled blood, carries a high risk of infection. The aim of this project is to develop a mouse model for haemophilia, in which proposed gene therapy protocols can be studied. To do this I have proposed to use homologous recombination to disrupt the endogenous factor VIII and IX genes in murine embryonic stem cells. Correctly targeted cells would be introduced into a developing mouse embryo where they would contribute to the germline and subsequently to a line of transgenic, haemophilic mice. As a first step towards this model, genomic bacteriophage libraries have been screened for the murine factor VIII and IX genes. Five bacteriophage clones were isolated and shown to contain the mouse factor IX gene. This locus has subsequently been characterised by dideoxy-sequencing and bacteriophage mapping methods. The mouse factor IX gene spans more than 53kb and shares, in the coding regions, 86% sequence identity with the human gene. The structure of mouse factor IX is discussed. No factor VUI-containing clones have been isolated, although sequences thought to be part of the murine factor VIII gene have been amplified by reverse transcription/PCR. Targeting constructs have been produced which contain part of the mouse factor IX gene disrupted by the selectable Neo cassette, and the HSV-tk gene which will allow the use of positive/negative selection procedures. These constructs have been introduced into the Embryonic Stem Cell line, E14, by electroporation, but no targeting events have yet been identified. 2 TABLE OF CONTENTS ABSTRACT OF T H E S I S ..................................... 2 TABLE OF CONTENTS....................................... 3 LIST OF F I G U R E S ......................................... 7 LIST OF TABLES 8 ACKNOWLEDGEMENTS 9 AIMS 10 1 GENERAL INTRODUCTION................................. 12 1.1 HAEMOPHILIA .................................. 13 1.2 THE COAGULATION C A S C A D E ..................... 14 1.3 THE FACTOR IX PR O T E I N ........................ 18 1.3.1 Synthesis and Structure of Factor IX . 21 1.3.2 H o m o l o g y ............................... 29 1.4 THE STRUCTURE OF HUMAN FACTOR V I I I ............ 30 1.5 THE FACTOR IX GE N E ............................. 34 1.5.1 The factor IX gene Promoter.......... 36 1.5.2 Exon A r r a n g e m e n t ..................... 40 1.5.3 Introns And Repetitive Elements .... 41 1.5.4 Splice S i t e s ......................... 42 1.5.5 3' Untranslated R e g i o n .............. 42 1.6 THE FACTOR VIII GE N E ........................... 43 1.7 MUTATIONS .................................... 47 1.7.1 Population Genetics ................... 48 1.7.2 Mutational Hotspots ................... 4 9 1.8 TREATMENT .................................... 51 1.8.1 Current M e t h o d s....................... 51 1.8.2 Future Prospects ..................... 53 2. TRANSGENESIS......................................... 57 2.1 INTRODUCTION OF DNA INTO E M B R Y O S.............. 59 2.1.1 Retroviral Infection ................ 59 2.1.2 Microinjection....................... 61 2.2 STEM C E L L S ................................... 62 2.2.1 Embryonal Carcinoma Cells ............ 63 2.2.2 Embryonic Stem C e l l s ................. 64 3 3. HOMOLOGOUS RECOMBINATION............................ 67 3.1 HOMOLOGOUS RECOMBINATION IN MAMMALIAN CELLS . 67 3.1.1 Chromosomal Targeting ................. 68 3.2 FACTORS AFFECTING THE FREQUENCY OF HOMOLOGOUS RECOMBINATION ............... 70 3.2.1 Vector D N A ............................ 70 3.2.2 Cell C y c l e ............................ 70 3.2.3 Length of H o m o l o g y .................... 71 3.2.4 Targeting of Non-expressed Genes . 71 3.3 INSERTION AND REPLACEMENT VECTORS ........... 73 3.4 METHODS OF T R A N S F E C T I O N ...................... 76 3.5 SELECTION PROCEDURES .......................... 77 3.5.1 E n r i c h m e n t ............................ 77 3.5.2 Selection............................... 79 3.6 THEORETICAL MECHANISMS ........................ 83 3.7 GERMLINE TRANSMISSION AND EXPRESSION OF A GENE CORRECTED BY HOMOLOGOUS RECOMBINATION IN EMBRYONIC STEM CELLS.......................... 89 4. MATERIALS AND M E T H O D S .............................. 92 4.1 MOLECULAR BIOLOGY............................ 94 4.1.1 T e c h n i q u e s ............................ 94 4.1.2 Buffers 116 4.2 TISSUE CULTURE............................... 126 4.2.1 T e c h n i q u e s .......................... 126 4.2.2 Buffers and Stock Solutions for Tissue C u l t u r e ............................... 130 5. ISOLATION OF THE MOUSE FACTOR VIII G E N E ........ 135 5.1 RESULTS ..................................... 136 5.1.1 Library screening ................... 136 5.1.2 Reverse Transcription/PCR .......... 138 5.1.3 Amplification from genomic DNA . 145 5.1.4 Direct Sequencing .................... 146 5.1.5 Cloning of PCR Products............. 148 5.2 DISCUSSION................................... 153 5.2.1 Library Screening ................... 154 5.2.2 Reverse Transcription /PC R .......... 158 5.2.3 Problems of Contamination ........... 160 4 5.2.4 Direct sequencing .................... 160 5.2.5 Cloning PCR P r o d u c t s ........... 161 5.2.6 Recent Developments ................. 162 6. ISOLATION AND CHARACTERISATION OF THE MOUSE FACTOR IX GENE 164 6.1 RESULTS ......................................164 6.1.1 Isolation of the Mouse Factor IX Gene 164 6.1.2 Mapping of the Mouse Factor IX Locus 165 6.1.3 Attempts to Isolate The Uncloned Regions of the Mouse Factor IX Gene...... 179 6.1.4 Sequencing of the Mouse Factor IX Gene 187 6.2 DISCUSSION.............................. 193 6.2.1 Bacteriophage Isolation ............. 193 6.2.2 The Mouse Factor IX Gene............. 194 6.2.3 Promoter R e g i o n ...................... 195 6.2.4 Transcription Start Point ........... 197 6.2.5 Translation.......................... 199 6.2.6 3' end of the Mouse Factor IX gene . 204 6.2.7 Attempts to Isolate the Uncloned Regions of the Mouse Factor IX Gene...... 205 7. TARGETING VECTOR CONSTRUCTION AND ELECTROPORATION EXPERIMENTS . 209 7.1 RESULTS ................................ 209 7.1.1 Targeting Vector .................... 209 7.1.2 Determination of Optimal Conditions for ES Cell Growth and Electroporation . 219 7.1.3 Gene Targeting E x p e r i m e n t s .... 233 7.2 DISCUSSION.............................. 239 7.2.1 Stem Cell C u lture.................... 239 7.2.2 Transfection Results ............... 241 7.2.3 Factors Affecting the Frequency of Homologous Recombination ............. 246 7.2.4 Alternative Strategies for Gene T a r g e t i n g ........................ 250 FUTURE W O R K ............................................ 256 REFERENCES ............................................ 259 5 APPENDICES I List of Abbreviations....................... 278 II List of Suppliers of Reagents.............. 282 III Addresses of S u p p l i e r s .................... 284 IV Buffers for Restriction Edonuclease Digests 285 V lkb Ladder .................................. 286 VI Oligonucleotide Sequences .................. 287 6 LIST OF FIGURES 1 Photograph of Haemophilia Patient ................. 12 2 The Coagulation Cascade ........................... 16 3 Amino Acid Sequence and Structure of Human Factor IX .................................................. 19 4 Sequence Homology of the Propeptides of the Vitamin K-dependent Proteins ............................... 22 5 Domain Structure and Processing of Human Factor IX................................................... 27 6 Domain Structure and Processing of Human Factor VIII ................................................ 32 7 Map of the X C h r o m o s o m e ........................... 35 8 The Human Factor IX G e n e ........................... 38 9 The Human Factor VIII G e n e ......................... 45 10 Disruption of the HPRT Gene by Gene Targeting . 74 11 The Positive/Negative Selection Procedure .... 80 12 Strategy for Detection of Homologous Recombinants by the Polymerase Chain Reaction...................... 82 13 The Holliday Model for Genetic Recombination . 85 14 The Meselson-Radding Model ...................... 86 15 The Double Strand Break Repair Model ........... 88 16 Outline of Proposed Strategy for Generating a Mouse Model for Haemophilia B (or A ) ................. 132 17 Genomic Southern Blot for Factor V I I I ......... 137 18 Diagram of Exons 8 and 9 of the Human Factor VIII
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