The sensation of smell enables us to gain valuable information about a plethora of chemicals in our immediate environment, and to respond appropriately. Olfactory receptor neurons (ORNs) are responsible for detection of these chemicals and are unique among neurons because following death due to cytotoxic insults or viral infections, they are replaced by new ORNs. This process occurs in the olfactory epithelium (OE) lining the nose and involves the step-wise transformation of mitotic basal (""""""""stem"""""""") cells into differentiated mature ORNs. In experiments outlined in this application, we will investigate the role of pituitary adenylate cyclase activating peptide (PACAP) in proliferation and maturation of normal developing and regenerating OE. PACAP is an intraepithelial peptide that acts as a cue for the regeneration of ORNs and for initiating defensive responses within ORNs to minimize cell death or apoptosis. The interaction of the signaling pathways activated by cell-extrinsic PACAP and cell-intrinsic electrical activity of ORNs in promoting differentiation of progenitor cells into differentiated ORNs will be investigated. In three specific aims, we will determine: (1) the expression profiles of PACAP and isoforms of its receptor (PAC1) in the developing and adult OE of wild-type and PACAP ko mice with and without bulb ablation; (2) the contributions of PACAP and cell-intrinsic activity in driving the maturation of ORNs and proliferation of basal stem cells, and (3) how PACAP prevents apoptosis of ORNs following cytokine inundation of the OE and injury caused by bulb ablation. Our studies are timely and critical for gaining an understanding of the cellular and signaling mechanisms involved in neuroregeneration in general, and are directly relevant to addressing the causes and potentials remedies of neurodegenerative diseases such as Alzheimer's and Parkinson's disease in which olfactory dysfunction is an early symptom.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC002994-06A2
Application #
6878242
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Davis, Barry
Project Start
1996-07-01
Project End
2009-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
6
Fiscal Year
2005
Total Cost
$328,900
Indirect Cost
Name
University of Utah
Department
Physiology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Ying, Guoxin; Avasthi, Prachee; Irwin, Mavis et al. (2014) Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J Neurosci 34:6377-88
Lucero, Mary T (2013) Peripheral modulation of smell: fact or fiction? Semin Cell Dev Biol 24:58-70
Saund, Ranajeet S; Kanai-Azuma, Masami; Kanai, Yoshiakira et al. (2012) Gut endoderm is involved in the transfer of left-right asymmetry from the node to the lateral plate mesoderm in the mouse embryo. Development 139:2426-35
Doucette, Wilder; Gire, David H; Whitesell, Jennifer et al. (2011) Associative cortex features in the first olfactory brain relay station. Neuron 69:1176-87
Kanekar, Shami; Gandham, Mahendra; Lucero, Mary T (2010) PACAP protects against TNF?-induced cell death in olfactory epithelium and olfactory placodal cell lines. Mol Cell Neurosci 45:345-54
Hegg, Colleen Cosgrove; Irwin, Mavis; Lucero, Mary T (2009) Calcium store-mediated signaling in sustentacular cells of the mouse olfactory epithelium. Glia 57:634-44
Han, P; Lucero, M T (2006) Pituitary adenylate cyclase activating polypeptide reduces expression of Kv1.4 and Kv4.2 subunits underlying A-type K(+) current in adult mouse olfactory neuroepithelia. Neuroscience 138:411-9
Vogalis, Fivos; Hegg, Colleen C; Lucero, Mary T (2005) Electrical coupling in sustentacular cells of the mouse olfactory epithelium. J Neurophysiol 94:1001-12
Han, P; Lucero, M T (2005) Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons. Neuroscience 134:745-56
Vogalis, Fivos; Hegg, Colleen C; Lucero, Mary T (2005) Ionic conductances in sustentacular cells of the mouse olfactory epithelium. J Physiol 562:785-99

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