The applicants 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 this Program 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. Project 1, Anti-Platelet Aggregation Therapy for Embolic Stroke, will investigate the mechanisms promoting secondary thrombosis after embolic stroke and treatment with rtPA in rat, and will test, in a controlled experimental model, treatment of embolic stroke with an antibody against the GPIIb/IIIa 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 multi-parameter MRI model to experimental embolic stroke in rats. The goals of this Project are to develop and test the application of the multi-parameter 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 II Pilot Clinical Trial of treatment of stroke with an anti-platelet aggregation agent, abciximab. This Project will test activity of treatment of the stroke patient with abciximab and will 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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