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DR3 Team and My Other Colleagues Within Medical Biochemistry and Medical Microbiology for Their Daily Advice and Entertainment The Role of Death Receptor 3 in Health and Disease A thesis submitted in candidature for the degree of DOCTOR OF PHILOSOPHY By Melanie Jane Bull January 2009 Medical Biochemistry and Immunology, Cardiff University, Wales College of Medicine Cardiff, CF14 4XN, UK. UMI Number: U584341 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. Dissertation Publishing UMI U584341 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed ................(Melanie Bull) Date M.J.ll.J.l.lQ.T.\.. STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD Signed . ............... (Melanie Bull) Date ..... STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed ................ (Melanie Bull) Date \cs!°.1..1.ZlX?.ca......... STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ............... (Melanie Bull) Date ....................................... STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Signed (Melanie Bull) Date Acknowledgements I would first like to thank my supervisors Dr Eddie Wang and Dr Anwen Williams for all of their advice, encouragement and hard work over the past few years. Your enthusiasm never failed to motivate me and without your support and patience throughout the ups and downs, I doubt this thesis would ever have been completed. I would also like to thank Dr Awen Gallimore for her involvement in the creation of the project. Secondly I would like to thank all of the members of the DR3 team and my other colleagues within Medical Biochemistry and Medical Microbiology for their daily advice and entertainment. I have thoroughly enjoyed my time within the lab and I would like to thank you all for making it a great experience. I would also like to thank the 13-IRG and the MRC for funding the project. Finally I would like to thank my family, Richard, Lloyd, Mum, Dad, Ellie, Mick and James, for their lifelong support and belief in me. I would especially like to thank my partner Richard and my son Lloyd for undertaking the whole experience with me. Despite the long hours and frustrations you kept me smiling through it all. Summary Death receptor 3 (DR3) is a death domain-containing type I transmembrane protein. It can bring about a wide range of responses from apoptosis to proliferation through association with intracellular signaling molecules. The only accepted ligand for DR3 is TNF-like protein 1A (TL1A). An important role for DR3 in inflammatory disease states is emerging with links being made with inflammatory bowel disease (IBD), Rheumatoid Arthritis, atherosclerosis, allergic lung inflammation and in renal inflammation. The project undertaken in this thesis investigated the role of DR3 in a murine model for rheumatoid arthritis, namely antigen-induced arthritis (AIA), using mice genetically deficient in DR3. A further aim of this project was to generate reagents for use in DR3 research through the employment of DR3 gene cloning strategies. DR3 deficient animals displayed a high degree of protection from mAIA in terms of resolution of joint swelling and the pathological degenerative alterations occurring within the joint. At day 21 post-arthritis induction, a time-point when maximal structural damage would likely be observed, DR37 animals showed a significant reduction in all histopathological parameters including a complete absence of bone erosion. This effect was shown to be DR3 specific through the administration of TL1A to control animals. Mice receiving increasing concentrations of TL1A showed a dose-dependent increase in synovial hyperplasia and bone erosion. DR3 deficient mice also displayed protection from cartilage depletion following induction of AIA. In an attempt to dissect a mechanism for this reduced disease severity, an analysis of osteoclast numbers and F4/80+ osteoclast precursor cell numbers within the joints was undertaken. DR3 sufficient mice displayed significantly more osteoclasts at sites of focal bone erosion which could not be attributed to differences in F4/80+ precursor cell numbers. The results presented here identify a potentially novel target for the treatment of human inflammatory joint disease. Table of contents Declaration ............................................................................................................................ i Acknowledgements ............................................................................................................ ii Summary ............................................................................................................................... iii List of tables.......................................................................................................................... xvii List of figures......................................................................................................................... xviii Suppliers and company addresses................................................................................... xxv Abbreviations ........................................................................................................................ xxvii 1. Introduction.......................................................................................................................... 1 1.1 The Tumour Necrosis Factor (TNF) Superfamily ........................................................... 2 1.1.1. General Structure of Receptors and Ligands ............................................ 2 1.1.2. Signalling........................................................................................................... 5 1.1.3. Knockout and Transgenic Models................................................................ 7 1.1.3.1. TNFRl/TNFct........................................................................................ 8 1.1.3.2. FAS......................................................................................................... 9 1.1.3.3. RANK..................................................................................................... 9 1.1.3.4. OPG..................................................................................................... 10 1.2 Death Receptor 3 .............................................................................................................. 10 1.2.1 Human DR3...................................................................................................... 10 iv 1.2.2 Murine DR3 ........................................................................................................ 12 1.2.3 Expression.......................................................................................................... 13 1.2.4 Signalling............................................................................................................ 14 1.2.5 The DR3 Ligand ................................................................................................. 18 1.2.6 DR3 knockout (DR3_/“) mouse model ............................................................ 20 1.2.7 In vivo Functions of DR3.................................................................................. 21 1.2.7.1 DR3 and Cancer ..................................................................................... 21 1.2.7.2 DR3 and Inflammatory Diseases........................................................ 22 1.3 The Normal Synovial Joint .............................................................................................. 24 1.3.1 The Synovial Capsule ....................................................................................... 25 1.3.2 The Synovium .................................................................................................... 25 1.3.3 Articular Cartilage ............................................................................................ 26 1.3.4 Bone .................................................................................................................... 27 1.3.5 Physiological Bone Remodelling ................................................................... 28 1.3.6 Osteoclasts......................................................................................................... 28 1.3.7 Osteoblasts........................................................................................................ 35 1.4 Rheumatoid Arthritis - Historical origin.....................................................................
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