This proposal signifies an expansion of my research efforts. My previous work has focused on defining early and late stages in the differentiation of olfactory sensory neurons, the capacity of the primary olfactory projection to recover from injury and the histopathology of human olfactory disorders. All three of these issues are enmeshed with the epithelium's unique capacity for neurogenesis throughout the life of the animal and for regeneration of the neuronal population after injury. This grant focuses on the biology of the basal cells in the olfactory epithelium, which are the neuronal precursor cells underlying the epithelium's neurogenic capacity. However, the regulation of olfactory neurogenesis is poorly understood at either a phenomenological or mechanistic level. The experiments proposed here seek answers to three questions about the basal cells of the olfactory epithelium. (1) Are basal cells functionally heterogenous with respect to their capacity to remain in the mitotic cycle? Their capacity as stem cells can be assayed by combining the sequential administration of 3H-thymidine and bromodeoxyuridine with an immunochemical definition of cellular phenotype. (2) What is the life history of individual basal cells? Genomic incorporation of a replication incompetent retroviral vector will be used to permanently label individual basal cells and their descendants, which will inherit this marker. (3) Can monoclonal antibodies be generated that will selectively mark basal cells and not neurons, and can ones be generated that will distinguish between various categories of basal cells? In contrast with previous attempts to answer this question, the immune response of the animal will be manipulated to focus more specifically on the basal cells, and the immunogen will consist of an enriched preparation of basal cells (partially purified either by """"""""panning"""""""" procedures or fluorescence activated cell sorting based on the incorporation of bromodeoxyuridine by dividing cells). Answers to these questions have implications for identifying how neurogenesis is regulated in the olfactory epithelium, for relating neurogenesis to sensory function, and for understanding those human olfactory diseases that are disorders of neurogenesis. In addition, collaborative arrangements are outlined that will enable me to acquire new training, including experience with molecular biological techniques. this additional training will prepare me for the pursuit of my long-term research objectives related to the cellular and molecular biological mechanisms regulating neurogenesis and neuronal differentiation in the olfactory epithelium.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Modified Research Career Development Award (K04)
Project #
5K04DC000080-03
Application #
2124443
Study Section
Sensory Disorders and Language Study Section (CMS)
Project Start
1992-12-01
Project End
1997-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Schwob, J E; Saha, S; Youngentob, S L et al. (2001) Intranasal inoculation with the olfactory bulb line variant of mouse hepatitis virus causes extensive destruction of the olfactory bulb and accelerated turnover of neurons in the olfactory epithelium of mice. Chem Senses 26:937-52
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
Huard, J M; Youngentob, S L; Goldstein, B J et al. (1998) Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non-neural cells. J Comp Neurol 400:469-86
Goldstein, B J; Fang, H; Youngentob, S L et al. (1998) Transplantation of multipotent progenitors from the adult olfactory epithelium. Neuroreport 9:1611-7
Ring, G; Mezza, R C; Schwob, J E (1997) Immunohistochemical identification of discrete subsets of rat olfactory neurons and the glomeruli that they innervate. J Comp Neurol 388:415-34
Goldstein, B J; Wolozin, B L; Schwob, J E (1997) FGF2 suppresses neuronogenesis of a cell line derived from rat olfactory epithelium. J Neurobiol 33:411-28
Youngentob, S L; Schwob, J E; Sheehe, P R et al. (1997) Odorant threshold following methyl bromide-induced lesions of the olfactory epithelium. Physiol Behav 62:1241-52
Loo, A T; Youngentob, S L; Kent, P F et al. (1996) The aging olfactory epithelium: neurogenesis, response to damage, and odorant-induced activity. Int J Dev Neurosci 14:881-900
Goldstein, B J; Schwob, J E (1996) Analysis of the globose basal cell compartment in rat olfactory epithelium using GBC-1, a new monoclonal antibody against globose basal cells. J Neurosci 16:4005-16
Huard, J M; Schwob, J E (1995) Cell cycle of globose basal cells in rat olfactory epithelium. Dev Dyn 203:17-26

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