My goal is to develop my career in academic neurology and to establish an independent investigation in the cellular and molecular mechanisms of cerebral ischemia. I will train under the sponsorships of Dr. John A. Wagner and Dr. Fred Plum. Dr Wagner, an expert in growth factor regulation of second messenger systems and immediate early gene induction, will provide me with an excellent laboratory environment to accomplish my objectives. In particular, I wish to develop research expertise using the techniques of biochemistry, molecular biology, and cellular biology. Dr. Plum, an authority on cerebral ischemia and coma, will provide me with superb clinical guidance. The research proposal will investigate the mechanisms of growth factor protection in stroke. Neuronal survival during cerebral ischemia is probably determined by a complex interaction between growth factors, neurotransmitters, and their respective signalling systems. Excessive release of excitatory amino acid neurotransmitters following an anoxic insult can result in neurite outgrowth as well as neuronal death. Basic fibroblast growth factor (beta-FGF) not only stimulates neurite outgrowth but also has recently been shown to be neuroprotective in animal models following a focal ischemic insult and in cell culture models with glutamate toxicity. The mechanisms by which beta-FGF protects neurons from ischemia is not known. Using primary cultures of hippocampal neurons, we will evaluate several potential cellular mechanisms that may contribute to the neuroprotective effects of beta-FGF during ischemic insults. The role of calcium homeostasis maintenance, inositol trisphosphate turnover, protein kinase C activation, glutamate receptor expression, cell glucose metabolism, and immediate early gene expression during anoxia will be studied. Dependent upon in vitro results, projected in vivo studies will evaluate the influence of beta-FGF on hippocampal glutamate receptor expression, cerebral glucose metabolism, and cerebral blood flow. The training will ultimately contribute to my understanding of cell death associated with cerebral ischemia and provide direction for therapeutic and preventive treatments against neurodegeneration.
