Phosphoinositide signaling in mammalian olfaction

描述（由申请人提供）：气味在我们的生活质量和健康中发挥着越来越重要的作用，这一作用受到疾病、药物、衰老和环境对嗅觉上皮的影响。由于嗅觉上皮中的嗅觉受体神经元（orn）为嗅觉系统提供主要输入，任何导致orn激活的细胞过程的破坏都不可避免地损害了嗅觉功能。这个项目建立在我们对嗅觉外围组织比最初想象的更复杂的新认识的基础上。它专门解决了这种复杂性中一个很大程度上被忽视的方面，即气味剂是如何抑制和激发rn的。它验证了基于越来越令人信服的数据的假设，即磷酸肌苷（PI）信号传导介导对哺乳动物rn的抑制性输入，并在设定天然复杂气味诱发的rn的输出中发挥重要作用。一系列重点的电生理、生化和分子实验通过继续评估PI信号在啮齿动物rn中的功能意义来解决这个问题，并开始确定PI信号作用的细胞机制。抑制性输入是通过一个不同的输入通路来调节的这个想法代表了对嗅觉的重要的新见解，这个见解不仅提出了关于OR本身本质的基本问题，而且还提出了抑制性输入对嗅觉编码的重要性，因为它有一个单独的信号通路。

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.