PROTEASE SIGNALING · Protease signaling in development and disease
FP7 — People (Marie Curie Actions)
- Duration
- 2009-12-01 → 2013-11-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
Lines connect the coordinator with its partners.
Results in brief
Protease signaling in development and disease.
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 with other signaling systems in a proposal aimed to explore novel roles for PARs in development and disease. We generated mice deficient in all PARs to uncover new roles for and activators of these receptors. This revealed new roles for PARs in embryonic development that had previously gone unnoticed due to redundancy within the family. A new role for PARs in neural tube closure helped us identify a proteolytic cascade that may engage these receptors during brain development as well as in skin disease. We are now further characterizing the molecular and functional basis for other roles for PAR signaling in mouse embryonic development. Addressing the redundancy with other receptor families we have focused on sphingosine-1-phosphate (S1P) signaling, as PARs and S1P receptors appear to interact in regulating vascular biology. We find that mice deficient in plasma S1P are sensitized to vascular leak and that PAR activation can rescue wild-type mice from lethal passive systemic anaphylaxis. By spatiotemporal genetic manipulation of S1P production as well as protease- and receptor- expression in mice we continue to explore the roles of S1P and PARs in the regulation of vascular biology and inflammation. In addition to improving our understanding of regulatory systems that contribute to embryonic development and regulation of cardiovascular development and homeostasis, these studies will inform on application of drugs in clinical development that modulate PAR and S1P signaling. Public website: http://parcc.inserm.fr/spip.php?rubrique20&lang=fr
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union