This interdepartmental, interdisciplinary program contains 9 component projects proposing to study the pathophysiology of acute cerebral ischemia, its molecular, biochemical correlates, and its consequences on brain function. A major goal will investigate cellular and biochemical events induced by ischemia-hypoxia and develop treatments to ameliorate this process. Investigators from Neurosurgery, Neurology, Radiology, or Medicine will share laboratory techniques, animal models, and equipment, and a core facility will promote this interaction. Individual projects propose to investigate the basis of ischemia-induced changes in the activities of cellular phospholipases (Bonventre, Peterson), calcium (Bonventre, Koroshetz), sodium-potassium ATPase (Sweadner), neuropeptides (Beal), induced proteins (heat shock, Bonventre), growth factors (Finkelstein), and brain pH and oxygen extraction fraction (Alpert). Two projects will examine the molecular responses of brain vessels (Finkelstein,Peterson). A testable hypothesis to be explored is that cerebral ischemia is accompanied by a definable metabolic and physiological cascade which develops over minutes to days. The detailing of these molecular events will facilitate the development of treatment strategies for stroke patients. Four animal models will be shared by 5 of the proposed projects: 1)temporary and 2)permanent rat middle cerebral artery occlusion, 3)ischemia and reperfusion in the gerbil; 4) chronically implanted cranial windows to study ischemia-induced angiogenesis. Experimental approaches will include the culturing of brain microvessel endothelial cells and cerebral neurons, patch-clamp, blot and in situ hybridization of RNA, an enzymatic analysis of ATP consumption by the Na pump,hplc determinations of inositol phosphates and neuropeptides, monoclonal antibody technology to probe brain proteins, receptor-binding assays, and positron tomography. We believe that a Program Project provides the most effective vehicle for developing multidisciplinary-multi- investigator approaches to the problem of stroke.
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