The goal of this research program is to develop a rapid, in vivo assay for screening small molecules for their ability to protect or regenerate neurons in a whole vertebrate organism. In Phase I, dopaminergic neurons in zebrafish embryos, made easily visible by transgenic incorporation of a fluorescent protein, will be exposed to the neurotoxin MPTP. Damage to neurons will be measured based on changes in fluorescence of the neurons. Molecules of known function, as well as novel molecules, will then be tested for their ability to protect neurons or promote neuronal growth in a dose-dependent fashion. Success in this endeavor can be accelerated to allow higher throughput screening in Phase II by using a high content fluorescent imager to quantify changes in fluorescence in a 96 or 384-well plate format. Molecules identified in this system have the potential to serve as novel drugs for the treatment of neurodegenerative diseases such as Parkinson's disease. No current treatments have been shown to prevent the progression of neuronal cell death in Parkinson's disease, increasing the need for innovation in drug discovery in this area. Since current high throughput technologies which utilize cells or explants in culture may not reflect the true in vivo environment, the zebrafish assay will represent a significant innovative advance in compound screening. of research to public health: The goal of this project is develop a fluorescent zebrafish assay to monitor damage to neurons induced by neurotoxins. Drugs that protect neurons from damage may be useful for the treatment of Parkinson's disease
