The long range goal of this research program is to identify and characterize the function of the olfactory marker protein (OMP) in the olfactory system. Expression of the OMP gene is developmentally regulated, phylogenetically conserved, and highly restricted to mature olfactory chemosensory neurons. The presence of this abundant 19kDa cytoplasmic protein in olfactory neurons in diverse vertebrate species is a hallmark of mature olfactory phenotype and strongly suggests that OMP has an important, but as yet undescribed, function in olfactory chemoreceptor neurons. The PI's laboratory has recently demonstrated a reproducible functional phenotype associated with this deletion of the OMP gene providing critical new information which suggests that this enigma can be solved. Olfactory neuroepithelium of mice devoid of OMP is deficient in electrophysiological responses to odor stimuli but morphologically normal. The olfactory bulb phenotype of these null mutants is strikingly similar to that of animals subjected to peripheral deprivation or deaferentation. Olfactory bulb mass is reduced as are athe levels of two gene products of intrinsic bulbar neurons. Taken together, these observations argue compellingly (1) that OMP participates in the process of signal detection or transduction of olfactory stimuli by olfactory neurons, and (2) that the bulbar phenotype is a result of reduced signal transmission in the bulb. These observations lead inescapably to the hypothesis that OMP interacts with other cellular components of the olfactory neuron to perform its function. Therefore, this study will utilize a combination of biochemical, molecular and physiological approaches to (1) identify, isolate, alone and characterize the molecules with which OMP interacts using the yeast two- hybrid system, and techniques of protein chemistry and immunoaffinity isolation, (2) determine the functional basis for the observed OMP- deficient phenotype using electrophysiology, and (3) analyze the OMP- deficient phenotype by in vitro or in vivo transfection with OMP expression vectors. These studies will provide definitive characterization of the mechanism by which OMP functions in olfactory neurons and generate novel, critical information about mechanisms of olfactory signal detection and transduction. They will provide insight into molecular aspects of olfactory perception and to the development of methods for intranasal therapeutic gene delivery to ameliorate deficits in olfactory function associated with aging or disease.
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