Role of alpha2-antiplasmin in wound recovery

Plasmin (Plm) plays a crucial role in blood clot dissolution (fibrinolysis), inflammation, cellular migration and wound healing. Alpha2-antiplasmin (AP) is the principal physiological inhibitor of Plm. AP, therefore, is indispensable in the restoration of haemostasis (stop bleeding) and controlling Plm activity; it also plays vital roles in immunity, and neurological developments and functions. However, high plasma levels of AP in humans have been linked to increased risk of ischemic stroke and failure of tissue plasminogen activator (tPA) therapy. Inactivation of AP activity is also shown to markedly reduce neurological damage and death associated with ischemic brain injury as well as pathological tissue repair upon severe injuries. We ask the question is AP indeed a better target for thrombotic diseases and recovery of an injury. Here, we will characterize the molecular interactions between AP and Plm and study the impact of AP inhibition in vitro. We will use crystallography, cryo-electron microscopy, enzyme kinetics and surface plasmon resonance to study AP inhibition. We will generate monoclonal antibodies and small-molecule inhibitors to block the AP/Plm interactions. High-affinity antibodies/inhibitors generated in these studies will be tested for their therapeutic potentials in animal model studies.