Phosphoinositide Signaling in Mammalian Olfaction

哺乳动物嗅觉中的磷酸肌醇信号转导

基本信息

批准号：
7470212
负责人：
Barry W. ACHE
金额：
$ 11.35万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-02-29
项目状态：
已结题

项目摘要

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.

气味在我们的整体生活质量和福祉中发挥着越来越重要的作用，这一作用疾病、药物、衰老和环境对嗅觉上皮的影响会损害嗅觉上皮。嗅觉上皮中的初级受体神经元具有检测和转导的关键功能气味刺激。任何导致受体细胞激活的细胞过程的破坏都会损害嗅觉功能。该项目所依据的新发现强调了早期的非决定性证据：气味剂激活哺乳动物嗅觉受体细胞的过程可能比原来赞赏。这些发现表明，阻断磷酸肌醇 3 激酶 (PI3K) 介导的磷酸肌醇信号通路的臂增强气味引起的细胞内钙的增加大鼠嗅觉受体细胞以气味特异性方式，并表明磷酸肌醇信号传导在气味编码的背景下调节哺乳动物嗅觉受体细胞的气味引起的兴奋。以气味特异性方式激活的第二个细胞内信号通路的存在将允许受体细胞真正整合信号，从而建立气味组合代码认可是有基础的。一系列集中的、主要是基于电生理学和成像的实验通过进一步表征阻断 PI3K 对大鼠反应的影响来解决这一新想法小鼠嗅觉受体神经元，通过开始表征 PI3K 的细胞机制调节细胞的输出，并进一步表征这种调节的功能意义。该项目的结果有望澄清磷酸肌醇长期被怀疑但难以捉摸的作用哺乳动物嗅觉中的信号传导，并提供对嗅觉作用的更完整的理解神经系统如何编码气味的外围。