Transgenic Mice for the Visualization of Dopamine Neurons in vivo

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurological disorder caused by the progressive degeneration of dopamine neurons within the substantia nigra region of the brain. The causes of this degenerative process have yet to be clearly determined, however, many types of compounds such as growth factors, and anti-apoptotic agents have been proposed to protect against the loss of dopamine neurons. A major impediment to the assessment of these compounds is the lack of an in vivo model assay system for high through-put evaluation. Currently, the testing of these compounds requires that the brains of each animal be processed and analyzed over several weeks before the effects of these compounds can be determined by the quantification of dopamine neurons within the substantia nigra. We propose a new approach where the dopamine neurons within the substantia nigra can be visualized and quantified in individual animals be creating transgenic mice that express the firefly enzyme luciferase. The expression of this enzyme will be restricted to cells within the body that produce the enzyme tyrosine hydroxylase, the rate limiting enzyme in the synthesis of dopamine. This restricted distribution will be accomplished by using the tyrosine hydroxylase promoter to drive the expression of the luciferase gene. Cell specific expression of luciferase will enable us to visualize the quantify dopamine neurons in the substantia nigra of living mice, and provide a high through-put assay for screening compounds that affect dopaminergic neuron degeneration and survival. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a neurological disorder characterized by tremor, rigidity, and bradykinesia. This is a progressively deteriorating condition that currently affects about 1.5 million people in the United States. At the present time, there is no cure for this disease. In our proposal, we intend to develop a line of transgenic mice that will enable us to visualize dopamine neurons in the living animal. Using this animal, we will be able to evaluate compounds that protect against dopamine neuron loss in a high throughput manner that will allow us to quickly screen many possible compounds. In addition, the development of this transgenic animal will allow us to study inductive cues that might be used to produce dopamine neurons that can be transplanted into patients with Parkinson's disease. As a consequence, this transgenic mouse could play an important role in developing new therapies for treating Parkinson's disease.