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Protease signaling in development and disease

Final Report Summary - PROTEASE SIGNALING (Protease signaling in development and disease.)


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.

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