Humans have approximately 400 functional olfactory receptors, but among this set there are a large number of variations between individuals. In some cases, these variations cause a receptor to be nonfunctional in a subset of the population. These variations likely underlie inter-individual variation in olfactory perception. Here we propose to identify ligands for odorant receptors, generate a library of odorant receptor variants and determine how responses to odorants are altered in the variants. The data generated in this proposal will be a critical step in our long-term goal to probe olfactory perception in humans by examining the perceptual correlates of these natural receptor variations. These studies lead to the hypothesis that variability in olfactory perception is caused in part by genetic dysfunction of olfactory receptors and that understanding the links between olfactory receptor variation and receptor function will reveal the underlying logic of the human odor code. To test this hypothesis, two specific aims are proposed:
Specific Aim 1 : Identify ligands for odorant receptors with segregating polymorphisms Specific Aim 2: Characterize the in vitro function and expression of common odorant receptor alleles. The proposed experiments further our long term goals to understand the logic of odor coding in humans.

Public Health Relevance

Deficits in the sense of smell are an early clinical sign for a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia. This proposal will provide insight for the design of more targeted tests of olfactory deficits that dissociate clinically relevant information from natural genetic variation. In addition the proposed experiments further our long-term goals to understand the logic of odor coding in humans.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Small Research Grants (R03)
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Special Emphasis Panel (ZDC1-SRB-R (37))
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Sullivan, Susan L
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Monell Chemical Senses Center
United States
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Mainland, Joel D; Li, Yun R; Zhou, Ting et al. (2015) Human olfactory receptor responses to odorants. Sci Data 2:150002
Mainland, Joel D; Keller, Andreas; Li, Yun R et al. (2014) The missense of smell: functional variability in the human odorant receptor repertoire. Nat Neurosci 17:114-20
Trimmer, Casey; Snyder, Lindsey L; Mainland, Joel D (2014) High-throughput analysis of mammalian olfactory receptors: measurement of receptor activation via luciferase activity. J Vis Exp :
Lunde, Kathrine; Egelandsdal, Bjorg; Skuterud, Ellen et al. (2012) Genetic variation of an odorant receptor OR7D4 and sensory perception of cooked meat containing androstenone. PLoS One 7:e35259
Adipietro, Kaylin A; Mainland, Joel D; Matsunami, Hiroaki (2012) Functional evolution of mammalian odorant receptors. PLoS Genet 8:e1002821
McRae, Jeremy F; Mainland, Joel D; Jaeger, Sara R et al. (2012) Genetic variation in the odorant receptor OR2J3 is associated with the ability to detect the ""grassy"" smelling odor, cis-3-hexen-1-ol. Chem Senses 37:585-93