Novel pathways and mechanisms underlying disorders of platelet count and/or function

About This Grant

PROJECT SUMMARY Our overall vision and long-term goal are to obtain a more complete understanding for how cellular signaling pathways, in particular G proteins and integrin receptors, control platelet adhesion and plug formation in hemostasis and thrombosis. Furthermore, we aim to elucidate aspects of the signaling machinery that function differentially in hemostasis versus thrombosis (both arterial and venous). The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism gone awry, and that disease-induced changes to platelet reactivity (priming) are a major contributor to thrombotic disease. A detailed understanding of platelet activation pathways is critical for the development of novel antithrombotic therapies, and for the identification of new biomarker assays for a prothrombotic state. Over the last two decades, my lab has utilized state-of-the-art in vitro and in vivo approaches to redefine our understanding of the molecular mechanisms regulating platelet reactivity in circulation and at sites of vascular injury. Key findings include the identification of tightly balanced G protein networks, an integrin activation complex that is unique to platelets, and injury-specific contributions of platelets to vascular integrity and thrombotic complications. The proposed work will focus on several areas within the general conceptual framework outlined above: (1) studies on G protein networks and integrin affinity regulation in platelets; (2) studies on the role of platelets in venous thrombosis pathogenesis and novel antithrombotic strategies; (3) development of novel assays to measure levels of primed platelets in different diseases; and (4) studies to better understand and correct defects in platelet count and function associated with inherited and acquired platelet disorders. Exciting preliminary findings include the identification of a novel G protein network in platelets, the establishment of new assays to monitor an elusive intermediate affinity conformation in platelet integrins, and a critical role for intermediate affinity integrins in thrombocytopenia and/or thrombosis associated with platelet disorders and cancer. In summary, the proposed studies will investigate significant knowledge gaps in basic platelet biology and provide a new understanding for how disease states like cancer affect platelet reactivity and platelet plug formation. Our studies have high translational relevance in the areas of antithrombotic therapy, biomarker development, and transfusion therapy.