PROTEASE SIGNALING

Protease signaling in development and disease

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 Obiettivo del progetto (Objective)

'Protease- activated receptors (PARs) comprise a family of four G-protein coupled receptors that mediate cellular responses to proteases. PARs were identified in a search for the platelet receptor for the coagulation protease thrombin. Mouse deficiency models later established critical roles for PARs in hemostasis and thrombosis and in vascular development, yet unexplained functions ascribed to proteases hinted at a broader functional repertoire. To uncover new roles for PARs, we addressed redundancy between PARs and found that combined loss of all PARs in mice resulted in embryonic lethality not accounted for by bleeding or lack of endothelial signaling, suggesting unappreciated roles for PARs in development. Addressing redundancy with other signaling systems, we found that loss of plasma sphingosine-1-phosphate (S1P), a lipid agonist for a related family of G-protein coupled receptors, had profound effects on endothelial barrier homeostasis including sensitization to barrier modulation by PARs. This proposal aims to explore a novel role for PARs in development of the cardiovascular system and to study the role of PARs and S1P receptors and their interaction in endothelial barrier homeostasis. Better understanding of PARs, their agonist proteases and redundant signaling systems in embryonic development and adult disease may refine the use of existing and emerging drugs targeting this system and, potentially, expand their application beyond current indications.'

Introduzione (Teaser)

Understanding how protease activated receptors (PARs) work during development was the key objective of a European proposal. The generated information has clinical implications especially in terms of drugs specifically targeting this system.

Descrizione progetto (Article)

PARs are transmembrane proteins that mediate signal transduction. They were initially identified in platelets and play a critical role in haemostasis, thrombosis as well as vascular development.

Scientists on the EU-funded 'Protease signaling in development and disease' (PROTEASE SIGNALING) project wished to uncover new roles for PARs in development and disease. To this end, they addressed the redundancy between the different PARs and how their loss could be compensated by another family member. Deletion of all PARs in a transgenic mouse model led to embryonic lethality which was not attributed to excessive bleeding or lack of endothelial signalling. This suggested that PARs play unappreciated roles in development. A new involvement of PARs in neural tube closure provided further evidence that these receptors are active during brain development.

To elucidate the interplay with other signalling systems, researchers deleted the ligand of a related family of receptors and assessed the impact of PARs. Animals lacking the related receptor could be rescued through PAR activation, verifying the redundancy between these two receptor types in regulating vascular biology.

The work of the PROTEASE SIGNALING project provided important knowledge on the regulatory systems that contribute to embryonic development. Furthermore, the generated information will be extremely useful in clinical drug development applications that modulate PAR signalling.