The protein C pathway: Mechanisms, Structure-function, and Translation

About This Grant

The long-term objectives of this program are to contribute to therapeutic progress for vascular, thrombotic, and inflammatory diseases by advancing knowledge through both basic and translational research. Available therapeutic solutions for cardiovascular diseases where vascular dysfunction underlies the disease etiology are limited and mortality rates remain unacceptably high. Despite recent advances, major gaps in knowledge remain about the physiological and pathophysiological mechanisms that are affected when vascular and inflammatory pathways intertwine with abnormal coagulation, which includes both hypercoagulation (thrombosis) and hypocoagulation (bleeding). Activated protein C (APC) is a naturally occurring anticoagulant plasma serine protease that has been translated to the clinic as a recombinant wild type or mutant biologic. Endogenous and pharmacologic APC has multiple beneficial effects in a diverse collection of preclinical animal injury models where unbalanced regulation of vascular, inflammatory, and coagulation pathways contribute to pathogenesis. These beneficial effects of APC are primarily mediated by the cytoprotective activities of APC that involve the endothelial protein C receptor (EPCR) and non-canonical activation of PAR1 at Arg46 and of PAR3 at Arg41, which induce biased signaling pathways contributing to rebalancing tissue homeostasis and host defense systems. Despite recent insights, there is a major gap in knowledge about protein-protein interactions between APC and its cellular receptors. Knowledge gathering on the Protein C pathway has a high likelihood for paradigm-shifting discoveries and for stimulating new basic and translational research directly relevant to NHLBI’s mission. This OIA program seeks a broad approach to advance basic knowledge possessing translational potential to fill major knowledge gaps. Building on our prior success, studies will continue our longstanding research focus in three related focus areas. The objective of focus areas 1 and 2 is to fill the major gap in knowledge about protein-protein interactions between APC and its substrates and cellular receptors. Mapping APC’s receptor specificities and understanding the structural requirements of the receptors will not only enable deciphering which receptors play critical roles on cells in vitro or in animals in vivo but also may lead to translation for novel APC mutants, APC mimetic peptides or other cytoprotection-promoting biologics. In focus area 3, we take a step back to consider the protein C pathway as the integrated part of hemostasis in the regulation of and response to thromboinflammation in the setting of a heightened prothrombotic state following a prior bacterial or viral infection. Succesful completion of this program will advance the field of blood and vascular disorders relevant to the mission of the NHLBI, will provide novel mechanistic insights for the protein C pathway biologics, and may aid translations of new biologics to the clinic.