A major opportunity for the post-genomic world will be to understand how the genome constructs the brain, and how this process goes awry in disease. The approach we are taking combines the computational procedures of biomedical imaging technologies, such as CT and PET, with high throughput methods to acquire 3D gene expression patterns in the brain. This new technology is called voxelation, and gets its name from the term """"""""voxel,"""""""" which refers to a cubic 3D image volume element. The voxel is the 3D analog of the familiar 2D image element, the pixel. Voxelation entails the direct creation of voxels (cubes) in spatial register with the brain, and application of high throughput gene expression analytic techniques to RNA extracted from the voxels. Imaging algorithms are then employed to reconstruct spatial information in high throughput. Using microarrays, we have obtained low resolution (40 voxel) images of the normal mouse brain for 9,000 genes, giving novel insights into the construction of the brain by the genome. Also using microarrays, we have acquired 2,000 gene, 24 voxel images of coronal hemisections of both normal and Alzheimer's disease human brains at the level of the hippocampus. Our analysis has revealed a common network of co-regulated genes, and allowed identification of putative control regions. In addition, a number of intriguing candidate genes have been found whose level of expression is significantly different between the Alzheimer's and normal hemisections. Finally, singular value decomposition (SVD), a mathematical technique used to provide parsimonious explanations of complex data sets, produced images that distinguished between brain structures, including cortex, caudate and hippocampus. Building on the foundations provided by these studies, voxelation will be employed in two Specific Aims using the mouse. (1.) Using microarrays, low resolution (40 voxel) high throughput (9,000) gene images of the brain will be acquired in four mouse models of human neuropsychiatric disorders: Parkinson's disease, drug addiction, schizophrenia, and dopamine D3 receptor deficiency. (2.) To extend the technology of voxelation, high resolution (300 voxel) moderate throughput (hundreds of gene) images of the mouse brain will be obtained using real-time quantitative RT-PCR. An instrument, the voxelator, has been constructed for semiautomated miniaturized harvesting of the voxels. Images from both Specific Aims 1 and 2 will be validated using classical techniques, such as in situ hybridization. This research promises important new insights into the nexus of genome and brain, in health and disease, and may also provide novel avenues to therapy.
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