The overall hypothesis of this proposal is that a multiprotein receptor complex on endothelial cells modulates plasma kallikrein-dependent activities that include blood pressure control, fibrinolysis, and angiogenesis, counterbalancing the renin angiotensin system. The basis of this hypothesis is the observation that when the proteins of the plasma kallikrein/kinin system (KKS), formerly called the """"""""contact activation system,"""""""" assemble on endothelial cells, prekallikrein (PK) is activated by the serine protease prolylcarboxypeptidase to form plasma kallikrein (KAL).
Specific Aim #1 : The structural basis of how cytokeratin 1 (CK1) complexes with the urokinase plasminogen activator receptor (uPAR) and gClqR and how these proteins interact with prolylcarboxypeptidase (PRCP) will be determined to understand how this receptor complex influences PK activation and plasma kallikrein-dependent activities.
This specific aim will test the hypothesis that variability of high molecular weight kininogen's interaction with the proteins of its multiprotein receptor complex, CKl-uPAR or CKl-gClqR, modulates plasma kallikrein formation and activity in the intravascular compartment.
Specific Aim #2 : The mechanism(s) of how high molecular weight kininogen (HK) and factor XII (FXII) influence uPAR-mediated signaling events in endothelial cells will be determined.
This specific aim will examine the hypothesis that kinin-free HK is antiproliferative and antiangiogenic by blocking single chain urokinase binding and mediated events in endothelial cells and FXII counterbalances the negative HK effects.
Specific Aim #3 : The ability of the plasma KKS to counterbalance the renin angiotensin system (RAS) will be examined in mouse models.
This specific aim will test the hypothesis that the plasma KKS counterbalances the plasma RAS in PRCP and PK knockout mice to regulate blood pressure and reduce thrombosis risk. The purpose of these investigations is to define physiologic activities of the plasma kallikrein/kinin system by showing its role in vascular biology. These investigations will lead to the recognition of new targets for drug development that could be used to treat hypertension and decrease thrombosis risk.
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