? This competing renewal (year 20) Program Project application pioneers the development of neurorestorative treatment of stroke and the application of magnetic resonance imaging (MRI) as a means to monitor neuronal and vascular structural changes in brain as they relate to functional improvement. Our preclinical data demonstrate significant improvement in neurological function after treatment of stroke in both young and old animals with sildenafil, a phosphodiesterase type 5 inhibitor which increases cyclic guanosine monophosphate (cGMP) in brain. To bring neurorestorative therapy to clinical fruition, we propose three highly integrated and longitudinally designed projects. Project 1 investigates with and without sildenafil treatment, the cellular and molecular mechanisms responsible for neuroblast proliferation in the subventricular zone of brain and their migration to the site of ischemia, the interaction of the microvasculature in the ischemic brain with these migrating neuroblasts, and the signal transduction pathways which mediate neurogenesis and angiogenesis. In Project 2, we translate the basic science in Project 1 into a preclinical study of restorative neurogenesis and angiogenesis in rodents subjected to embolic stroke and treated with sildenafil. In this project, we emphasize imaging of the neuronal and vascular remodeling processes in brain. We employ MRI, specifically, fractional anisotropy to image neuronal changes, and a cluster of MR methods to identify vascular remodeling in the ischemic brain. MRI indices of neuronal and vascular remodeling are thus related to functional and behavioral outcome, with the goal of developing MRI as a marker of recovery after stroke. We also develop novel approaches to measure neuroblast migration, and we employ two-photon laser scanning confocal microscopy to visualize in real-time vascular and neurite structure with the goals of developing neurorestorative treatment of stroke and obtaining fundamental and new information on the dynamic processes of brain remodeling post stroke. Project 3 is a Phase I safety clinical trial using sildenafil as a neurorestorative treatment of stroke patients with treatment administered within 7 days of stroke onset. As in Project 2, MRI will be employed to identify neuronal and vascular changes in the human brain and to relate these changes to functional recovery. The three projects are supported by three cores. Core A is the Administrative Core, Core B is the Statistical and Data Management Core and Core C is an Imaging Core. The long-term objectives of this Program Project are to develop neurorestorative therapy for stroke and MRI methods to noninvasively monitor neuronal and vascular changes reflecting recovery from stroke. Our studies are designed to improve neurological function and the management of the stroke patient. ?
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