The prior efforts of the applicant 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 signifies an expansion of the principal investigator's efforts and 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 heterogeneous 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) What is the role of the horizontal basal cell in the maintenance and reconstitution of the olfactory epithelium? Does this type of basal cell have the characteristics expected of a stem cell for the neuronal population of the epithelium? The principal investigator will determine if they are slowly proliferating cells that are recruited to divide in response to injury of the neuronal population. The principal investigator will also define the horizontal basal cells, and their relationships with other cells in the epithelium, at an ultrastructural level. 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.
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