The broad goals of this application are to identify mechanisms associated with the functions of the striatum under normal and pathological conditions. The striatum is the primary region of dysfunction in several neurodegenerative disorders, such as Huntington's and Parkinson's diseases, and is also associated with movement disorders and psychiatric disturbances. Presently, treatment strategies for these disorders are not curative, but rather are aimed at reducing symptoms. Hence, a better understanding of the mechanisms and pathways that contribute to striatal function is essential. The logic that has motivated our studies is that mRNA molecules with restricted expression in the striatum are likely to encode proteins that are preferentially associated with particular physiological processes of this region.
In Specific Aim 1, we will identify and isolate all known genes with specific or enriched expression in the striatum using the systematic, automated mRNA display technology TOGA (Total Gene expression Analysis). We will then create a cDNA microarray chip containing all known and newly discovered striatal-enriched species ( 100). This will provide us with a DNA tool for analyzing the expression status of all striatal-evident genes under various pathological conditions. In this application, we will focus on the pathology of Huntington's disease (HD), (although additional/future studies will investigate other striatum disorders). HD is an inherited, neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances.
In Specific Aim 2, we will identify genes associated with HD by screening the striatal-enriched DNA chip with RNA from the brains of transgenic HD mice. These mice express exon 1 of the human HD gene carrying an extremely expanded CAG repeat. Finally, we will test the hypothesis that the HD gene product, huntingtin, interacts with proteins that are enriched in the striatum, hence, giving rise to the tissue-specific degenerative patterns observed in this disease. We will screen all striatum-enriched proteins simultaneously for specific interactions with both normal and mutated forms of the huntingtin. This will be achieved by creating a protein microarray chip containing GST-fusion proteins of each striatal-enriched gene and then probing with biotinylated-labeled huntingtin. The molecules identified in these studies could targets for novel therapies that would prevent or slow the onset of symptoms as well as the progression of Huntington's disease, and very well may lead to cures for this and other devastating neurodegenerative disorders. An important advantage of these potential pharmaceutical targets is that they would act only at the restricted site of expression, the striatum.
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