This program project seeks to identify the genes, mRNAs and proteins that establish the phenotypic characteristics that distinguish the cellular elements (i.e., neuron subsets, or """"""""types"""""""") within defined regions and nuclei of the rodent brian. Many brain-specific or enriched genes and gene products await discovery and characterization. Therefore, the goals of this continuation application are focussed upon discovery strategies that will optimize detection of functionally responsive genes and gene products. To reach this objective we will apply recombinant DNa, and genetic technologies to isolate the cDNA clones of brain mRNAs identified through their spatial distribution or through their sequence-specific hybridization with nucleic acid probes devised within the Buchmeier, Milner, Peterson and Sutcliffe Components to reflect unique functional properties according to their individual strategic protocols. The Bloom component will employ immunological, immunocytochemical, and in situ hybridization methods to map the mRNAs and their gene products at the regionally selective developmental expression and extend these subtractive hybridization approaches to the rodent hypothalamus and to the repair processes that follow central axotomy or cns infection with the Mouse Hepatitis Virus, or its reduced virulence deletion mutants. We shall identify and characterize the rodent substance K receptor gene and compare it with other tachykinin and G-protein coupled receptors. We will employ stem cell gene disruption and transgeneic expression to evaluate changes in brain structure or function when cells that normally express selected genes are prevented from doing so. We will characterize the altered gene products and spatially map the affected cells. We will relate our data to known brain molecules and cells, and seek to define the functional properties of the molecules identified and the cell types and cell systems that express them. We view the identification of functionally unknown brain specific genes and gene products as a critical step in fully understanding brain physiology and the pathophysiology of presently isoluble neurologic and psychiatric disorders.
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