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Relative roles of cell surface IP versus intracellular nuclear receptor PPARbeta in the sensing and signalling of prostacyclin

Ziel

Prostacyclin is a powerful endogenous mediator involved in the regulation of a number of essential biological processes.

Key functions of prostacyclin include:
(1) inhibition of platelet aggregation,
(2) vasodilatation,
(3) inhibition of vascular cell proliferation and inflammation and
(4) reduction of cholesterol accumulation.

Prostacyclin and its metabolites are clinically used to inhibit platelet aggregation (if heparin is contraindicated) and to treat pulmonary hypertension. Indeed, it is the only medication for PAH that has shown a survival benefit in a randomised clinical trial. Prostacyclin is produced by endothelial cells following the consecutive actions of cyclo-oxygenase and prostacyclin synthase. The actions of prostacyclin are mediated by two receptor classes: cell surface IP receptors, linked to adenylate cyclase, and nuclear receptor PPARbeta which regulates the transcription of several target genes to mediate cellular responses. Most recently we have shown that PPARbeta is active in platelets, which have no nucleus, suggesting that it may also have non- genomic effects.

The relative roles of IP versus PPARbeta in the sensing and signalling of prostacyclin by tissues of the cardiovascular system is not known. In the current application we seek to use selective pharmacological tools and cells from genetically modified mice (where IP or PPARbeta have been knocked-out) to firmly identify how IP and PPARbeta receptor systems act and interact when cells or platelets are treated with prostacyclin and related compounds.

Wissenschaftliches Gebiet (EuroSciVoc)

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Aufforderung zur Vorschlagseinreichung

FP6-2005-MOBILITY-5
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Finanzierungsplan

EIF - Marie Curie actions-Intra-European Fellowships

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IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
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