This application seeks renewal of the National Institute of Mental Health Silvio Conte Center for Neuroscience Research at Caltech. The Center brings together eight research groups and continues to emphasize cellular and molecular signaling as the basis for neuronal function in the central nervous system. In the next phase of operation, there will be an added an emphasis on molecules and pathways that were first identified in the context of developmental signaling. The central hypotheses emphasize both unity and diversity. It is suggested (1) that most classes of signaling protein--7-helix receptors, G proteins, enzyme effectors, kinases, ligand-gated channels, voltage-gated channels, transporters, receptor tyrosine kinases and phosphatases, integrin receptors, DNA- binding proteins, and others now being discovered--participate in several distinct types of signaling pathways within neurons; and (2) that the complexity and diversity of molecular and cellular signaling pathways accounts for much of the functional diversity of CNS neurons. The range of favorable preparations constitutes a strength of the Center and includes: rat CNS neurons in slices, organotypic cultures, and dissociated cultures; rat olfactory epithelium in primary culture; human olfactory neuroblastoma; mammalian cell lines; neural crest cells in primary culture; embryonic stem cells transfected with genes of interest; transgenic mice and tissues and cells from these mice; Xenopus oocytes expressing signaling proteins; Xenopus eyes and brains; and bacteria expressing G proteins. These questions are being investigated with a variety of appropriate technical approaches that promise rapid progress. The range includes: nucleic acid molecular biology; heterologous expression in mammalian cells via adenovirus; heterologous expression in oocytes; transgenic, knockout and knock- in mice; protein chemistry; electrophysiology; immunocytochemistry; optical recording of intracellular ions; confocal and 2-photon imaging; and bacterial genetics. Research on the cellular and molecular basis of neuronal function is relevant to mental diseases, to neurological diseases, and to substance abuse.
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