This project will make use of a new method for functionally expressing members of the odor receptor gene family. An adenovirus vector will be utilized to drive over expression of cloned receptors in mice, where they can be assayed for their specific odor affinities. In this way the """"""""molecular receptive field"""""""" of these receptors will be defined for a set of odorant ligands. Receptors with related gene sequences will be screened to determine if they also recognize related or overlapping sets of odor ligands. Because the cells expressing the cloned receptors also express GFP it is possible to record from identified single cells dissociated from the olfactory epithelium. With single cells stimuli of carefully controlled concentration and duration can be delivered, allowing for the development of dose response relations for each of the ligands that a receptor may be able to bind. It will further aid in the identification of potential antagonists and other molecular competitors that may act at these receptors. Antagonists are an important tool in the studying structure function relations between receptor and ligand. The overall aim of the project is to understand in some detail how the thousand or so odor receptors manage the task for detecting and discriminating some 10,000 odor ligands. By focusing on a subset of these receptors in the mouse, where it is possible to correlate these data with information from genetically targeted animals, it is expected that some general principles will emerge, both at the molecular level of the odor receptor protein, and at the systems level of olfactory coding. Odor receptors comprise the largest family of G-protein couple receptors in the mammalian genome. As such they represent a kind of """"""""natural"""""""" experiment in which variations in receptor structure due to differences in amino acid sequence can be related to alterations in receptor-ligand affinity. Because the odor receptors are in the same genetic superfamily of receptors as those for neurotransmitters, hormones, drugs and many peptides, understanding the relationship between structure and function in these receptors could lead to important new principles for rational drug design and for receptor modifications. Many neurological diseases are the result of deficient receptors for neurotransmitters or neurohormones. These results will speak directly to those causes.
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