The GNRC unites three groups studying the neurobiology and pathophysiology of schizophrenia with a core of scientists in the Columbia Genome Center (CGC) working on """"""""genomic"""""""" strategies to identify schizophrenia-related genes. These GNRC has two major objectives. The first goal is to elucidate the neurobiological underpinnings of schizophrenia, including neurochemical abnormalities (in synaptic proteins and MAP2), and neuroimmunological abnormalities (relating to the immunogenicity of an abnormal chaperonin, hsp60). The key genes, proteins, protein-protein interactions, and regulatory mechanisms generated by these and other studies then provide the template for the first of two computational genomic """"""""search engines"""""""". The first engine is designed to elaborate biochemical and regulatory pathways by predicting novel protein-protein interactions based upon systematic phylogenetic homology searchers. By matching human genes and proteins with their orthologues in lower, well-characterized organisms, new patterns of interaction can be predicted. These new """"""""protein networks"""""""" thereby form a database of likely target genes for schizophrenia-related DNA alterations. The second goal of the GNRC is to combine molecular and computational strategies to systematically identify and characterize all genes in a given large schizophrenia-linked chromosomal region. A second """"""""search engine"""""""" will collect all genes and predicted genes from such regions and characterize their phylogenetic homology relationships. Simultaneously, we will use established high throughout technologies to sequence large segments of the linked regions and analyze for predicted protein coding regions. Together, these strategies will yield a new set of gene and protein sequences that form a positional candidate gene database. Next, the protein-interaction and positional candidate search engines will cross- analyze to predict high priority candidate genes. In the final phase of the proposal we will develop a strategy to DNA sequence multiple candidate genes in a collection of patient and control DNA samples. In this way we will generate a public database of schizophrenia-related DNA alterations that will lay the foundation for a DNA microchip assay for large samples. A significant feature of this """"""""genomic"""""""" search strategy is that it bypasses the necessity of detecting shared chromosomal segments, the basis of all current genetic search strategies.
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