Necessary steps towards understanding the sense of smell include characterizing the relevant molecular components that regulate olfactory sensory neuron (OSN) responses and analyzing behaviors of animal models that harbor abnormal odor coding. Our initial studies in mice suggest that Cilia- and Flagella-Associated Protein 69 (CFAP69), an evolutionarily conserved and poorly studied protein, plays a critical, yet unconventional, role in regulating olfactory transduction kinetics, odor stimuli coding of OSNs and also olfactory behavior. CFAP69 is enriched in OSN cilia, where olfactory signal transduction occurs. OSNs from CFAP69 conditional knockout mice display faster response kinetics in both on- and off- phases of the response with little change in response size, and can fire action potentials more faithfully to repeated stimuli than the control OSNs. CFAP69 conditional knockout mice, despite having higher temporal resolution in coding odor stimuli at the peripheral sensory neuron level, performed inferiorly in a challenging olfactory task. In this proposal, we will: 1) Determine the role of CFAP69 in regulating OSN sensitivity, adaptation and action potential coding by detailed electrophysiological analysis of odor responses at the levels of intact olfactory epithelium and isolated single cells from OSN-specific conditional knockout mice; 2) Investigate the mechanisms by which CFAP69 exerts its effect by using both a combined pharmacological and electrophysiological approach to determine the site of CFAP69 action in the transduction cascade and a biochemical approach to identify its interaction protein partners; and 3) Investigate how altered OSN response and odor stimuli coding affect olfactory behavior in OSN-specific conditional knockout mice. The proposed research will bring new knowledge and new perspective to the understanding of the olfactory transduction process, olfactory stimuli coding of OSNs and olfactory perception. The research will enhance our understanding of the fundamental biology of olfaction and olfactory dysfunction.