Phosphoinositide Signaling in Mammalian Olfaction

描述（由申请人提供）：气味在我们的一般生活质量和健康中发挥着越来越重要的作用，这种作用受到疾病，药物，衰老和环境对嗅觉上皮冲击的影响。嗅上皮中的初级受体神经元具有检测和传导气味刺激的关键功能。任何导致受体细胞活化的细胞过程的破坏都会损害嗅觉功能。该项目所基于的新发现强调了早期的非决定性证据，即气味剂激活哺乳动物嗅觉受体细胞的过程可能比最初认识的更复杂。这些研究结果表明，阻断磷酸肌醇-3激酶（PI 3 K）介导的臂的磷酸肌醇信号通路增强气味诱发的增加，在大鼠嗅觉受体细胞的细胞内钙在气味特异性的方式，并建议磷酸肌醇信号调节气味诱发的兴奋哺乳动物嗅觉受体细胞的气味编码的背景下。以气味特异性方式激活的第二种细胞内信号传导途径的存在将允许受体细胞实际上整合建立气味识别所基于的组合密码的信号。一系列集中的，主要是电生理和成像为基础的实验解决了这一新的想法，通过进一步表征阻断PI 3 K对大鼠和小鼠嗅觉受体神经元的反应的影响，通过开始表征PI 3 K调节细胞输出的细胞机制，并通过进一步表征这种调节的功能意义。该项目的结果有望澄清长期怀疑的磷酸肌醇信号在哺乳动物嗅觉中的作用，并提供对嗅觉外周在神经系统编码气味中的作用的更完整的理解。

DESCRIPTION (provided by applicant): Odors play an increasingly appreciated role in our general quality of life and well being, a role that is compromised by the effect of disease, drugs, aging and environmental onslaught on the olfactory epithelium. Primary receptor neurons in the olfactory epithelium serve the critical function of detecting and transducing odor stimuli. Disruption of any of the cellular processes leading to receptor cell activation would impair olfactory function. New findings on which this project is built underscore earlier, inconclusive evidence that the process by which odorants activate mammalian olfactory receptor cells may be more complex than originally appreciated. These findings show that blocking the phosphoinositide-3 kinase (PI3K)-mediated arm of the phosphoinositide signaling pathway enhances odorant-evoked increases in intracellular calcium in rat olfactory receptor cells in an odorant-specific manner, and suggest that phosphoinosotide signaling modulates odorant-evoked excitation of mammalian olfactory receptor cells in the context of odorant coding. The presence of a second intracellular signaling pathway activated in an odorant-specific manner would allow the receptor cell to actually integrate the signal that establishes the combinatorial code on which odor recognition is based. A series of focused, primarily electrophysiological and imaging-based experiments address this novel idea by further characterizing the effect of blocking PI3K on the response of rat and mouse olfactory receptor neurons, by beginning to characterize the cellular mechanisms by which PI3K modulates the output of the cells, and by further characterizing the functional significance of this modulation. The results of the project can be expected to clarify the long-suspected, but elusive role of phosphoinositide signaling in mammalian olfaction, and provide a more complete understanding of the role of the olfactory periphery in how odorants are encoded by the nervous system.