A better understanding of the pathophysiological mechanisms underlying human olfactory dysfunction is obviously important for improving the clinical management of dysosmic patients. To that end we have been evaluating the histopathology to the human olfactory mucosa, and have been using that information to construct animal models of olfactory disease. This project continues our efforts and has the following Specific Aims; (1) To increase the available information regarding the histopathology of the olfactory mucosa in a variety of clinical settings, paying particular attention to (a) preservation of the neuronal population, (b) neuronal maturation, (c) aberrant axonal growth, (d) proliferation rate, (e) cell death. We will be focussing specifically on the mechanisms of epithelial regression (which we term quiescence), the type of neuronal damage in post- URI patients, and the pathology associated with phantosmia. (2) To identify the mechanism underlying epithelial regression in an animal model of human quiescence, namely mice made transgenic for an OMP-SV40 T antigen construct. During regression, we will analyze basal cell proliferation, neuronal lifespan and neuronal differentiation in order to achieve that aim. In parallel with the anatomical analyses, we will monitor the functional consequence os epithelial regression by assessing both behavioral performance on a 5 odorant identification task and the patterns of inherent mucosal activity as a function of age. (3) To assess whether IGF-1 will serve as a survival factors and extend the lifespan of olfactory neurons born in the absence of the olfactory bulb, on which the neurons are trophically dependent. At least in part, several forms of dysosmia are due to a lack of axonal connection between the epithelium and bulb and the accelerated turnover of neurons that occurs as a consequence. IGF-I- containing pellets will be implanted into the ablation cavity after bulbectomy and neuronal life-span will be determined by following the cohort of neurons labeled at birth via the incorporation of thymidine and by following the set of neurons labeled after axonal growth into the ablation cavity via the retrograde transport of fluorescent beads. (4) To assess whether transplanted basal cells will incorporate into the epithelium of a lesioned host and generate neurons, and whether those neurons will survive, differentiate and connect with the olfactory bulb. At least two forms of olfactory pathology --the permanent replacement of olfactory by respiratory epithelium and the regression of the olfactory epithelium -- are probably due to destruction or exhaustion, respectively, of the epithelium's neurogenic potential. Transplanted cells will express beta-galactosidase as a heritable marker, which will allow us to recognize them ad their progeny in the host tissue; heritability ill be conveyed by germline incorporation of the transgene or by infection of basal cells with a replication-incompetent retrovirus. Successful completion of these aims will provide substantial insight into the pathophysiology of human olfactory disease and open avenues for potential therapeutic intervention.

Project Start
1998-04-01
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Type
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Youngentob, Steven L; Schwob, James E (2006) Odorant identification and quality perception following methyl bromide-induced lesions of the olfactory epithelium. Behav Neurosci 120:1346-55
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Hornung, D E; Smith, D J; Kurtz, D B et al. (2001) Effect of nasal dilators on nasal structures, sniffing strategies, and olfactory ability. Rhinology 39:84-7
Kurtz, D B; Sheehe, P R; Kent, P F et al. (2000) Odorant quality perception: a metric individual differences approach. Percept Psychophys 62:1121-9
Kurtz, D B; White, T L; Hayes, M (2000) The labeled dissimilarity scale: a metric of perceptual dissimilarity. Percept Psychophys 62:152-61
Schwob, J E; Youngentob, S L; Ring, G et al. (1999) Reinnervation of the rat olfactory bulb after methyl bromide-induced lesion: timing and extent of reinnervation. J Comp Neurol 412:439-57
Kurtz, D B; White, T L; Hornung, D E et al. (1999) What a tangled web we weave: discriminating between malingering and anosmia. Chem Senses 24:697-700

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