Human olfaction provides a unique window into understanding normal brain function. Odorous chemicals in the environment are detected by a large family of canonical odorant receptors, and a much smaller family of Trace Amine-Associated Receptors (TAARs). There are only 6 intact TAARs in humans and the TAARs are conserved in many vertebrate species, suggesting a common, important function. However, very little is known about the functional properties of human TAARs due to the limitations of current methods to express odorant receptors in cell culture systems. Here we propose to circumvent these issues by functionally expressing all of the human TAARs in mouse olfactory sensory neurons in vivo.
Specific Aim 1 is to generate a set of gene-targeted mouse strains in which each of the human TAARs is expressed in a defined population of fluorescently labeled olfactory sensory neurons.
Specific Aim 2 is to functionally characterize human TAARs by recording electrophysiological responses from TAAR-expressing olfactory sensory neurons in these mice. These studies should allow us to identify for the first time ligands for the human TAARs, and should shed light on how the TAAR genes contribute to human olfaction.
Olfaction, the sense of smell, contributes significantly to quality of life and overall human health by allowing humans to detect and avoid harmful chemicals and spoiled food. We propose to use mouse genetics to circumvent a long-standing hurdle in the field and to thereby characterize the function of human olfactory receptors under the most physiologically relevant conditions possible. Our experiments should shed light on the molecular mechanisms by which humans recognize amines, a class of malodorous chemicals that are released during the putrefaction of tissues and food sources due to microbial activity.
