Biology Alpha2 Antiplasmin Research Proposal
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.
Biology Alpha2 Antiplasmin Research Proposal
Keywords
fibrinolysis, protease, structural biology, X-ray crystallography, stroke, injury, wound healing, department of biochemistry and molecular biology
Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a serine protease inhibitor (serpin) responsible for inactivating plasmin.[5] Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.
Role in disease
Very few cases (<20) of A2AP deficiency have been described. As plasmin degrades blood clots, impaired inhibition of plasmin leads to a bleeding tendency, which was severe in the cases reported.
In liver cirrhosis, there is decreased production of alpha 2-antiplasmin, leading to decreased inactivation of plasmin and an increase in fibrinolysis. This is associated with an increase risk of bleeding in liver disease.
