The aim of this research is to understand the roles of inositol polyphosphates and their specific binding proteins in controlling the homestasis of calcium in brain. It is known that brief excitotoxic insults to hippocampal pyramidal cells causes their demise, but only days after the insult. This observation raises the possibility that medical treatments might be developed which could be administered after a stroke, seizure, or heart attack to reduce the subsequent delayed neuronal damage. The biochemical events occurring between the insult and the death are not understood, but involve aberrations in calcium homeostasis. The proposed experiments will use fluorescent imaging to examine normal and pathological calcium dynamics in cultured neuronal and glial cells. To understand the molecular mechanisms underlying the responses, the focus will b GAP1IP4BP, an inositol tetrakisphosphate (IP4) binding protein that interacts with the Ras signalling pathway. This protein lies at a crucial branch point in cellular signalling and may link the changes in intracellular calcium after toxic insuts to the subsequent death of neurons. Initial studies will establish expression levels of GAP1IP4BP and IP4 levels in the cultured cells. Neurons and glia will then be microinjected with blockers and stimulators of the GAP1IP4BP signal transduction pathways, and the spatiotemporal changes in intracellular calcium dynamics will be visualized in individual cells. Once the normal calcium response neurons is characterized, the cells will be exposed to excitotoxic insults and then injected with various molecular probes of the IP4 signal transduction pathways in an attempt to modify the calcium dynamics.
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