The peripheral olfactory neuroepithelium is able to regenerate after injury; however the signals that initiate the complex cascade leading to increased cell proliferation and neurogenesis are poorly understood. We will examine ATP as an important local trophic factor in injury-evoked olfactory neuron regeneration. We hypothesize that noxious insult to the olfactory epithelium triggers an extracellular ATP-induced signaling cascade that initiates regeneration of the neuroepithelium. We base this hypothesis on the observation that (1) cell damage, iysis and also regulated processes will release ATP into the extracellular milieu and (2) activation of purinergic receptors induces synthesis and/or release of neurotrophic factors, mitogenesis, and differentiation in the CNS. Thus, ATP released by acutely injured cells could stimulate localized regeneration due to the mitogenic and growth-promoting effects of purinergic receptor activation. Growth promotion can be mediated by G protein coupled purinergic receptors located on sustentacular support cells and basal stem cells, which, like other growth factor receptors, induce a cascade of intracellular events that trigger cell proliferation.
Our specific aims are to (1) Determine if noxious and physiological stimuli evoke release of ATP in the OE. We will identify toxicological and physiological stimuli, pathways of release and sources of ATP using bioluminescence assays and confocal microscopy. (2) Determine if extracellular ATP and purinergic receptor activation elicits the release of neurotrophic factors. We will measure ATP-induced increases in membrane capacitance as an indication of exocytosis, vesicular release of ATP, and release of neurotrophic factors using electrophysiology, confocal microscopy and immunocytochemistry. (3) Determine if extracellular ATP and activation of purinergic receptors elicits proliferation. We will determine if ATP is sufficient to initiate proliferation or acts synergistically to initiate proliferation in the uninjured olfactory epithelium, and/or promotes injury-evoked proliferation using immunohistochemistry and in vitro and in vivo assays. This data will clearly have implications for the pharmacological modulation of proliferation. Agents that modify the effects of purinergics and purinergic receptors are readily available and could therapeutically modulate cell proliferation and differentiation, in the olfactory system and in the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC006897-04
Application #
7328850
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Davis, Barry
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-08-17
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$215,201
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Jia, Cuihong; Hegg, Colleen C (2015) Effect of IP3R3 and NPY on age-related declines in olfactory stem cell proliferation. Neurobiol Aging 36:1045-56
Jia, Cuihong; Hayoz, Sebastien; Hutch, Chelsea R et al. (2013) An IP3R3- and NPY-expressing microvillous cell mediates tissue homeostasis and regeneration in the mouse olfactory epithelium. PLoS One 8:e58668
Hayoz, S├ębastien; Jia, Cuihong; Hegg, Cc (2012) Mechanisms of constitutive and ATP-evoked ATP release in neonatal mouse olfactory epithelium. BMC Neurosci 13:53
Jia, Cuihong; Hegg, Colleen Cosgrove (2012) Neuropeptide Y and extracellular signal-regulated kinase mediate injury-induced neuroregeneration in mouse olfactory epithelium. Mol Cell Neurosci 49:158-70
Jia, Cuihong; Sangsiri, Sutheera; Belock, Bethany et al. (2011) ATP mediates neuroprotective and neuroproliferative effects in mouse olfactory epithelium following exposure to satratoxin G in vitro and in vivo. Toxicol Sci 124:169-78
Jia, C; Cussen, A R; Hegg, C C (2011) ATP differentially upregulates fibroblast growth factor 2 and transforming growth factor ? in neonatal and adult mice: effect on neuroproliferation. Neuroscience 177:335-46
Jia, Cuihong; Roman, Carlos; Hegg, Colleen C (2010) Nickel sulfate induces location-dependent atrophy of mouse olfactory epithelium: protective and proliferative role of purinergic receptor activation. Toxicol Sci 115:547-56
Jia, Cuihong; Hegg, Colleen Cosgrove (2010) NPY mediates ATP-induced neuroproliferation in adult mouse olfactory epithelium. Neurobiol Dis 38:405-13
Hegg, Colleen C; Jia, Cuihong; Chick, Wallace S et al. (2010) Microvillous cells expressing IP3 receptor type 3 in the olfactory epithelium of mice. Eur J Neurosci 32:1632-45
Kanekar, Shami; Jia, Cuihong; Hegg, Colleen Cosgrove (2009) Purinergic receptor activation evokes neurotrophic factor neuropeptide Y release from neonatal mouse olfactory epithelial slices. J Neurosci Res 87:1424-34

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