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Title: Protease-activated receptor-2 in arthritis : in vivo investigations
Author: Palmer, Helen Suzanne.
ISNI:       0000 0001 3465 6276
Awarding Body: University of the West of Scotland
Current Institution: University of the West of Scotland
Date of Award: 2007
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The emerging role of protease-activated receptor-2 (PAR2) in chronic joint inflammation may present therapeutic opportunities for the treatment of diseases such as rheumatoid arthritis (RA). The central hypothesis examined in this thesis was that PAR2pathways playa key role in the pathogenesis of RA. Although there is increasing interest in the involvement of PAR2in joint inflammation, the proinflammatory mechanisms and the importance of this receptor in RA remain unclear. The role of PAR2 was investigated in vivo with the specific aim of characterising the upstream activation mechanisms and downstream proinflammatory mechanisms of PAR2 in joint inflammation, and assessing whether PAR2-dependent pathways present a novel therapeutic avenue in a T cell driven, murine model of rheumatoid arthritis. Chapter 3 explores endogenous and exogenous activators of PAR2 in the context of joint inflammation. Agonist responses are characterised and used to assess the potency and specificity of the first PAR2 antagonist (ENMD-1068). This was an important prelude to work presented later in the thesis and the conclusion of these studies was that ENMD-1 068 is a selective but low-potency antagonist for PAR2. Although earlier proof of concept studies have shown the presence of functional PAR2 to be crucial to the chronicity of a murine model of RA, the therapeutic potential of inhibiting PAR2in a highly relevant model of the disease has yet to be assessed. The studies presented in chapter 4 show not only that a novel PAR2 antagonist, ENMD1068, has therapeutic efficacy in ameliorating collagen-induced murine arthritis (CIA), but also, importantly, that PAR2antagonism suppresses release of the proinflammatory cytokine TNFa by T cells in this model of RA. Mast cells and PAR2 are independently reported to be important in models of RA but the mechanisms by which they contribute to the disease require elucidation. Since mast cells are known to be abundant in the inflamed j oint and are capable of releasing tryptase, a potent and preferential activator of PAR2, a functional link between mast cells and PAR2 seemed plausible. Indeed, mast cell tryptase is a likely candidate as a key endogenous activator of PAR2in arthritis. Chapter 5 explores the relationship between mast cells, tryptase and PAR2, and presents the first evidence for a functional link between mast cells and PAR2in the context of the joint. In addition these studies sought to clarify the downstream proinflammatory mechanisms of PAR2and demonstrates that prostaglandins are, in part, responsible for the pro-inflammatory actions of PAR2in the murine joint. Collectively the studies presented in this thesis support a key role for PAR2in arthritis, and extend the field by providing novel insights into the mechanisms by which PAR2 pathways contribute to joint inflammation. Perhaps most importantly, this work advances the case for the therapeutic potential of inhibiting PAR2pathways and supports progression towards future clinical trials of PAR2 inhibiting agents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available