The olfactory epithelium is renowned for its capacity to recovery after injury. Nonetheless, disrupted regeneration causes clinical disease. Previous work by the Principal Investigator suggests that the basal cell population in the adult harbors progenitor cells with the capacity to found neuronal and non-neuronal lineages when they are activated by damaged to the olfactory epithelium. The applicant proposes to extend his previous work by addressing the following hypotheses. (1) His previous observations suggest that there are two fundamental lineages in the olfactory epithelium. He will test the hypothesis that the multipotent progenitor is a kind of globose basal cell (GBC) and the duct/gland progenitor is a duct cell. A further corollary of this model is that cells that are ostensibly further downstream are more restricted in their developmental potential. (2) Evidence indicates that there are multiple kinds of GBCs that range from multipotent progenitors to others that have only a limited capacity for proliferation before completing terminal differentiation. The applicant proposes to test the hypothesis that the expression of the cell surface antigen recognized by a set of monoclonal anti-GBC antibodies, GBC-1, GBC-2, GBC-3, mark the transition from one functional state to another during the progressive restriction of fate that occurs as the epithelium recovers after injury. (3) The applicant will also test whether they are active constitutively and their fate is redirected as a consequence of the epithelial milieu. These hypotheses will be tested within the context of two Specific Aims.
Specific Aim 1 will use a set of anti-GBC antibodies to define specific populations of GBCs, and assess their significance by comparing them to marker that are functionally relevant, including transcription factors and measures of proliferative activity.
Specific Aim 2 will use a transplantation assay by analogy to the CFU-S assay that revolutionized our understanding of hematopoiesis. The Principal Investigator will determine, first the progenerative capacity of marker-defined subsets of GBCs as well as other epithelial cell types that proliferate and, second, where regulation as being exerted to control that progenerative capacity. Successful completion of the Aims will greatly improve our understanding of the regenerative capacities of the olfactory epithelium (a process termed epitheliopoiesis) and of the pathophysiology underlying olfactory dysfunction.
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