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。由于嗅觉上皮中的嗅觉受体神经元（ORN）提供嗅觉系统的主要输入，导致ORN激活的任何细胞过程的破坏不可避免地损害嗅觉功能。该项目建立在我们新的认识之上，即嗅觉外围的组织比最初认识到的更加复杂。它具体解决了这种复杂性中一个很大程度上被忽视的方面，即气味剂如何能够抑制和激发ORN。它测试的假设，建立在越来越令人信服的数据，磷酸肌醇（PI）信号介导的抑制性输入哺乳动物的ORN，并发挥了重要作用，在设置输出的ORN诱发的天然，复杂的气味。一系列的重点，电生理，生物化学和分子实验解决了这个问题，继续评估PI信号在啮齿动物ORN的功能意义，并开始确定PI信号工作的细胞机制。抑制性输入是通过一条与兴奋性输入不同的输入途径来介导的，这一观点代表了对嗅觉的重要新见解，这一见解不仅提出了关于OR本身性质的基本问题，而且还提出了关于抑制性输入对嗅觉编码的重要性的基本问题，因为它有一条单独的信号通路。 公共卫生相关性：据估计，1%的65岁以下人口和至少50%的老年人表现出可检测到的嗅觉丧失。气味激活嗅觉受体细胞的任何细胞事件的中断，例如本研究的目标事件，都会中断对大脑的嗅觉输入。因此，详细了解气味如何激活嗅觉受体细胞对于有效解决痴呆症等疾病以及与嗅觉功能障碍相关的生活质量下降至关重要。

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. As olfactory receptor neurons (ORNs) in the olfactory epithelium provide the primary input to the olfactory system, disruption of any of the cellular processes leading to the activation of the ORNs inevitably compromises impairs olfactory function. This project builds on our emerging understanding that the organization of the olfactory periphery is more complex than originally appreciated. It specifically addresses a largely ignored aspect of that complexity, which is how odorants are able to inhibit as well as excite ORNs. It tests the hypothesis, built on increasingly compelling data, that phosphoinositide (PI) signaling mediates inhibitory input to mammalian ORNs and plays an important role in setting the output of the ORNs evoked by natural, complex odorants. A series of focused, electrophysiological, biochemical, and molecular experiments address this question by continuing to evaluate the functional significance of PI signaling in rodent ORNs, and beginning to identify the cellular mechanisms through which PI signaling works. The idea that inhibitory input is mediated through a distinct input pathway from that mediating excitation represents important new insight into the sense of smell, insight that not only raises fundamental questions about the nature of the OR itself but also about the importance of inhibitory input to olfactory coding in having a separate signaling pathway assigned to it. PUBLIC HEALTH RELEVANCE: An estimated 1% of the population under the age of 65 and at least 50% of older individuals demonstrate detectable smell loss. Disruption of any of the cellular events by which odors activate olfactory receptor cells, such as the events that are the target of this research, disrupt olfactory input to the brain. A detailed understanding of how odors activate olfactory receptor cells therefore is critical to effectively address disease states such as dementia and the diminished quality of life associated with olfactory dysfunction.