Tuesday, April 23, 2024
4/23/2024
PROJECT SUMMARY All currently available antithrombotic medications carry the risk of hemorrhage, an often devastating complication in many patients that can rapidly reverse the benefits of therapy. Given this reality, coagulation factor XII (FXII) has emerged as a promising new drug target that could potentially transform antithrombotic therapy. Blockade or deletion of FXII in preclinical animal models has consistently been shown to be protective against thrombosis, yet severe congenital FXII deficiency is not associated with a bleeding diathesis. Therefore, inhibiting FXII could represent the long-sought means to “decouple” hemostasis from thrombosis and achieve antithrombotic efficacy without bleeding complications. However, despite its potential clinical importance, little is known about the mechanisms underlying platelet-dependent FXII activation in vivo. Using a mass spectrometry proteomic screen, we have identified integrin aIIbß3 as the putative platelet receptor for FXII. These results have been followed up with a number of additional studies reproducibly demonstrating the FXII-integrin aIIbß3 interaction. Our central hypothesis is that FXII zymogen exhibits specific binding to integrin aIIbß3 on the platelet surface, which enhances its proteolytic activity and is necessary and sufficient for FXII-dependent coagulation. In Aim 1 of this proposal, we will map the region(s) of FXII responsible for binding to integrin aIIbß3 via competitive inhibition assays using recombinantly-generated fragments of FXII. We will also utilize surface plasmon resonance to evaluate the specificity of the FXII- integrin aIIbß3 interaction and obtain binding kinetics. In Aim 2, we will explore the role of integrin aIIbß3 binding in the activation of FXII using integrin aIIbß3-coated beads and platelets from wild- type and integrin ß3 (ITGB3)-null mice. The proposed work will provide important new insights into the molecular mechanism of FXII recruitment, activation, and propagation at the platelet surface and inform efforts to develop novel therapeutics based on FXII inhibition.
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