OMP--ROLE IN OLFACTORY SIGNAL DETECTION AND TRANSDUCTION

这项研究计划的长期目标是确定和 描述嗅觉标记蛋白（OMP）的功能， 嗅觉系统 OMP基因的表达受发育调节， 遗传上保守，高度局限于成熟的嗅觉 化学感受神经元 这种丰富的19 kDa细胞质的存在 不同脊椎动物嗅觉神经元中的蛋白质是 成熟的嗅觉表型，并强烈表明OMP具有重要的， 但尚未被描述，在嗅觉化学感受器神经元中的功能。 PI的实验室最近证明了一种可重复的功能性 与这种OMP基因缺失相关的表型提供了关键的 新的信息表明这个谜可以被解决。 嗅觉 缺乏OMP的小鼠的神经上皮缺乏电生理功能， 对气味刺激有反应，但形态正常。 嗅球 这些无效突变体的表型与动物的表型惊人相似 受到边缘性的剥夺或者被剥夺生育能力。 嗅球肿块 降低了内源性延髓的两种基因产物的水平 神经元 综合起来，这些观察令人信服地认为（1）， 外膜蛋白参与细胞信号的检测或转导过程， 嗅觉神经元的嗅觉刺激，以及（2）延髓表型 是灯泡中信号传输减少的结果。 这些观察结果不可避免地导致OMP相互作用的假设 与嗅觉神经元的其他细胞成分一起执行其 功能 因此，本研究将利用生物化学， 分子和生理学方法来（1）鉴定、分离、单独和 表征分子与OMP相互作用使用酵母双- 杂交系统、蛋白质化学和免疫亲和技术 分离，（2）确定观察到的OMP的功能基础- 缺陷表型使用电生理学，和（3）分析OMP- 通过体外或体内转染OMP表达的缺陷型 向量。 这些研究将通过以下方式提供该机制的明确表征： OMP在嗅觉神经元中发挥作用， 关于嗅觉信号检测机制的信息， 转导 他们将提供深入了解分子方面的 嗅觉和鼻内检测方法的发展 改善嗅觉功能缺陷的治疗性基因递送 与衰老或疾病有关。

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.