? Every year, over 750,000 people in the USA experience a stroke, contributing to over 167,000 deaths. What is needed are effective and safe therapies to help improve and save these lives. It was recently found that Apo E2 and E4 can modulate tissue plasminogen activator (tPA) induced clot lysis in vitro. This proposal tests the hypothesis that specific regions of Apo E2 and E4 isoproteins interact with factor(s) of the clot formation/degradation cascade and can modulate thrombolytic-induced clot lysis via two distinct aims.
Aim 1 is to determine the activity of Apo E isoforms on clot degradation induced by several thrombolytics and thromboembolic therapies using the in vitro clot lysis assay that we developed, along with a commercially available finbrin D-dimer assay.
Aim 2 is to characterize the intermolecular interactions of ApoE and clotting factor(s) using enzyme overlay assays and circular dichroism (CD). The results will determine how the ApoE isoproteins interact within the clotting cascade to modulate clot formation/lysis. The long term goal of this proposal is to use this information to develop Apo E, or fragments thereof, to specifically modulate clot lysis, making thromboembolic/thrombolytic therapies safer and more effective. ? ?
