We propose a highly integrated application focused on preclinical and clinical studies to investigate and develop treatment of stroke with an anti-platelet aggregation agent alone and in combination with thrombolysis using recombinant tissue plasminogen activator (rtPA). Permeating our efforts, is the development and application of MRI to enhance the management of the stroke patient. Three interdependent Projects and two Cores constitute this grant application. In Project 1 """"""""Anti-Platelet Aggregation Therapy for Embolic Stroke,"""""""" we investigate the mechanisms promoting secondary thrombosis after embolic stroke and treatment with rtPA in rat, and we test, in a controlled experimental model, treatment of embolic stroke with an antibody against the GPIIb/nia receptor. This receptor binds the platelet to fibrin and is responsible for platelet aggregation and therefore, platelet mediated thrombosis. This project leads into Project 2, """"""""MR Assessment of Transient Cerebral Ischemia,"""""""" which develops and applies a multiparameter MRI model to experimental embolic stroke on rat. The goals of this Project are to develop and test the application of the multiparameter MRI model to identify candidates for therapy and to exclude candidates from therapy after embolic stroke. In addition, the MRI response to thrombolysis with rtPA and rtPA in combination with an antagonist to platelet aggregation will be tested. Projects 1 and 2 form the preclinical support for a Phase n Pilot Clinical Trial of treatment of stroke with an anti-platelet aggregation agent, abciximab. In this Project, we test activity of treatment of the stroke patient with abciximab. We identify an MRI based surrogate marker for activity and accrue MR data to select patients for anti-platelet aggregation therapy. Core A is an Administrative and Biostatistical Core. Core B, the MRI core, services all three Projects. The Program Project provides an integrated highly coherent effort to enhance management and therapeutic intervention in the treatment of acute stroke.
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