EXCEED THE SPACE PROVIDED. fire and in the consumption of food. Perturbations of the olfactory system cause loss of appetite and poor nutrition, IpaIrntichulmaralynsw, itheolsdenrsepaotifenstms.ellFoisr cerxitaimcapllfeo,r tphreotaevcetiroangeaghauinmsat nexlotesrensala hsaigzanrifdicsanint cplurdoipnogrtion orf tghaesir, olfaction as they age, and olfactory dysfunction is associated with several aging-related diseases including Alzheimer's and Parkinson's disease. Olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) are constantly insulted by exogenous stress which includes exposure to volatile toxic chemicals and bacterial infections. The olfactory system has the exquisite capacity to discriminate between an immense variety of odorants. Furthermore, OSNs in the MOE exhibit a number of short-term and long-term adaptive changes in response to odorant exposure. This grant focuses on mechanisms that mediate the detection of odorants and contribute to transcription-dependent, long-term adaptive responses in the MOE. it is our hypothesis that cAMP signals generated through odorant activation of the type 3 adenylyl cyclase (AC3) play a key role in olfaction. We propose that termination of AC3 activity by calmodulin-dependent protein kinase II (CaMKII) contributes to olfactory-based behavioral responses including chemotaxis to odorants. We also propose that cAMP and Ca2+-mediated activation of the CREB/CRE transcriptional pathway by odorants mediates long- term adaptive responses in the MOE including odorant-induced activity-dependent survival of OSNs and proliferation of immediate neuronal precursors. This general hypothesis will be examined using inducible transgenic mouse strains lacking AC3 and calmodulin-dependent proteins kinase II activities as well as adenovirus-mediated expression of dominant-negative and constitutive-active MEK and CREB in the MOE. These studies should provide fundamental information concerning neuronal signaling mechanisms in the OSNs, and may ultimately provide new insights concerning clinical and pharmacological strategies to )revent anosmia associated with aging, bacterial infections, and neurodegenerative diseases. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Davis, Barry
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University of Washington
Schools of Medicine
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Chen, Xuanmao; Luo, Jie; Leng, Yihua et al. (2016) Ablation of Type III Adenylyl Cyclase in Mice Causes Reduced Neuronal Activity, Altered Sleep Pattern, and Depression-like Phenotypes. Biol Psychiatry 80:836-848
Cao, Hong; Chen, Xuanmao; Yang, Yimei et al. (2016) Disruption of type 3 adenylyl cyclase expression in the hypothalamus leads to obesity. Integr Obes Diabetes 2:225-228
Stratigopoulos, George; Burnett, Lisa Cole; Rausch, Richard et al. (2016) Hypomorphism of Fto and Rpgrip1l causes obesity in mice. J Clin Invest 126:1897-910
Wang, Wenbin; Lu, Song; Li, Tan et al. (2015) Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function. J Neurosci 35:7833-49
Chen, Xuanmao; Cao, Hong; Saraf, Amit et al. (2015) Overexpression of the type 1 adenylyl cyclase in the forebrain leads to deficits of behavioral inhibition. J Neurosci 35:339-51
Liu, Jack J; Chan, Guy C; Hecht, Avi S et al. (2014) Nasal saline irrigation has no effect on normal olfaction: a prospective randomized trial. Int Forum Allergy Rhinol 4:39-42
Liu, Jack J; Chan, Guy C; Hecht, Avram S et al. (2014) Comparison of two nasal cell collection methods in determining cyclic adenosine monophosphate levels and its association with olfaction: A feasibility study. Allergy Rhinol (Providence) 5:17-21
Zou, Junhui; Storm, Daniel R; Xia, Zhengui (2013) Conditional deletion of ERK5 MAP kinase in the nervous system impairs pheromone information processing and pheromone-evoked behaviors. PLoS One 8:e76901
Li, Tan; Pan, Yung-Wei; Wang, Wenbin et al. (2013) Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb. PLoS One 8:e61948
Chen, Xuanmao; Xia, Zhengui; Storm, Daniel R (2013) Electroolfactogram (EOG) Recording in the Mouse Main Olfactory Epithelium. Bio Protoc 3:

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