The proposed research will develop and optimize a discovery platform for new targets in the central nervous system (CNS). The developed platform, combining laser capture microdissection (LCM) with cDNA microarray analysis, will allow for the gene expression profiling of identified neuronal subtypes within the CNS. The discovery platform will provide for the dissection and harvesting of identified neuronal subtypes from their native environment and the comprehensive analysis of gene expression in the targeted neurons. The platform is dependent on the effective joining of two techniques; LCM and gene expression profiling by oligonucleotide and cDNA microarray probe sets. The overall aim of the present proposal is to optimize this union. The approach is dictated by the pharmaceutical industry need for new CNS drug targets and the impenetrable nature of the CNS given its extreme cellular heterogeneity.The ultimate commercial aim of the approach is to sell/license high quality, validated CNS drug targets and their associated chemical leads to the pharmaceutical industry. The optimized CNS drug discovery platform will serve as a standardized method for expanding molecular drug targets within the CNS. It will be able to interface with any neuronal identification technique such as BAC transgenes, immunofluorescence, neuronal tracers, etc. The commercial value of the platform will be realized through the quality of the molecular targets and the chemical leads against these targets provided by the approach. It is expected that the completion of this Phase I proposal will result in a reliable and flexible discovery platform. Deployment of the approach for new target discovery will occur in Phase II.
