Role of death receptor 3 in health and disease

Bull, Melanie Jane 2009. Role of death receptor 3 in health and disease. PhD Thesis, Cardiff University.

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Abstract

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.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303186011
Date of First Compliant Deposit:	30 March 2016
Last Modified:	09 Jan 2018 22:18
URI:	https://orca.cardiff.ac.uk/id/eprint/55813

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