Olfactory marker protein (OMP) is an abundant, olfactory neuron specific, phylogenetically conserved cytoplasmic protein of unknown function. To address its function, the PIs have generated mice lacking the gene for OMP by targeted-gene deletion and homologous recombination in embryonic stem cells. Although the development and overt behavior of these animals appear to be normal, physiological, biochemical, and psychophysical analyses demonstrate a constellation of defects which suggest that OMP is a novel modulatory component of the odor detection/signal transduction cascade. Thus, the PIs propose to apply a set of interdisciplinary techniques (i.e., selective gene deletion by homologous recombination, psychophysical behavioral analysis, and adenoviral vector-mediated gene expression) to characterize in detail the behavioral phenotype resulting from OMP gene deletion and to """"""""rescue"""""""" it by delivering an OMP- adenovirus expression vector. Specifically, the PIs will: (1) test the hypothesis that OMP gene deletion results in a generalized elevation in odorant threshold sensitivity (i.e., reduced sensitivity), as measured by performance on an odor threshold task, and if so, whether it can be reversed by adenoviral vector-mediated expression of OMP; (2) test the hypothesis that the response to above threshold concentrations of odorant is altered in animals lacking OMP, as measured by a reaction time index of sensory function, and if so, whether they can be rescued by vector-mediated expression of the protein; and (3) test the hypothesis that odorant quality perception is altered in OMP-null animals, as measured by performance on a five odorant identification tasks. In summary, the results of these studies will provide direct in vivo support for the hypothesis that OMP is an important component in the odor detection/signal transduction cascade. In addition, they will define the functional consequences of OMP loss on olfactory processing (i.e., determine whether OMP is critically involved to the extent that its loss will influence function). Thus, these studies will allow us to further refine our understanding of OMP's role in odor processing. As an additional benefit, the approach defined in this proposal will establish a framework for future evaluations of function in animals where the transduction process has been altered through targeted-gene deletion. The information gathered from these integrated studies will improve our understanding of a potential etiology of human olfactory dysfunction (i.e., at the transduction level) and may provide insight into a therapeutic strategy that has implications for a variety of neurological disorders.
