Paracrine Control Systems Laboratory
Research
We have developed an alternative view as to roles of protease-activated receptors (PARs), particularly those located on barrier cells of the body – the epithelial and endothelial cells – that are often faced with potentially harmful environments. We believe that PARs located on these ‘frontline’ cells act as sensors of inflammation and respond by activating a range of anti-inflammatory mechanisms that in concert provide an ‘umbrella’ of protection of both the barrier cells themselves and the underlying tissues. We have already demonstrated that airways epithelial PAR2, and to a lesser extent PAR1, are bronchoprotective. From these and other studies, we have proposed that selective activation of barrier cell PARs represent new strategies for anti-inflammatory therapies. Honours student Christine Koulis is investigating the role of PAR2 in the inflammatory skin disorders and skin grafting.
Dr Cocks and Dr Devlin are involved in a start-up company, Pargenex Pharmaceuticals Pty Ltd, operating within the Department that has developed new anti-inflammatory drugs for a variety of diseases. As well as producing structure-activity profiles on these novel synthetic PAR agonists using an assay of cell calcium mobilisation, Pargenex is also testing their therapeutic potential in mouse models of colitis, arthritis and asthma.
Ongoing techniques in our laboratories include immune cell trafficking, epithelial ion transport, smooth muscle reactivity, receptor turnover, in vivo and in vitro measurements of vascular and airways smooth muscle reactivity, confocal immunohistochemistry, enzymography and Ca2+ fluorescence imaging.
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Key References
* Moffatt JD, Jeffrey KL, Cocks TM. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am J Respir Cell Mol Biol. 2002;26:680-684.
* Cocks TM and Moffatt JD. Protease-activated receptors: sentries for inflammation? Trends Pharmacol Sci. 2000;21:103-108.
* Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, Henry PJ, Carr MJ, Hamilton JR and Moffatt JD. A protective role for protease-activated receptors in the airways. Nature. 1999;398:156-160.
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