The last several years have witnessed a molecular revolution in the olfactory system. The turning point in this revolution was the seminal discovery, now seven years ago, of a large multigene family in mammals that encodes odor receptors. However, the molecular biology of odor receptors has not been fully integrated with the anatomy and the physiology of the olfactory system. We are aware that the expectations raised by the isolation of odor receptor genes have yet to be fully realized. We have concluded that it is imperative that we begin now to explore the relations between the molecular specificity at the level of the olfactory sensory neuron, the specificity of anatomical organization among the glomeruli in the olfactory bulb and finally, the parameters that may influence the intracellular distribution and dynamics of odor receptor proteins. The present application seeks support for an innovative collaborative program in which all of the investigator share common aims and reagents. Each project brings to the program a unique expertise that enables us to test, from multi-disciplinary perspectives, specific hypotheses regarding the molecular mechanisms of odor coding and mapping. A common theme is the use of genetically engineered mice. Project 1 addresses functional specificity of odor receptors by using and constructing gene-targeted strains of mice. Project 2 uses gene-targeted mice to assess the specificity of synaptic circuits in the olfactory bulb, and gene transfer approaches to identify the parameters that may influence odor receptor protein targeting within the sensory neuron. Project 3 uses adenoviral vectors and gene-targeted mice to characterize the determinants of odorous ligand binding to specific odor receptors. Targeted mutagenesis in the mouse, molecular biology, calcium imaging, advanced anatomical techniques, and novel brain imaging methods are merged in this consortium of laboratories with different backgrounds and expertise. Collectively, we anticipate that this focused and multi- disciplinary set of projects will lead to significant advances in understanding the mechanisms of odor coding and mapping.
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