Renal Olfactory Receptor 90: ligands, localization and function

 描述(申请人提供)：近年来，嗅觉受体(ORs)被证明在鼻子之外扮演着各种重要的角色，作为化学传感器帮助肌肉迁移、精子趋化性和代谢物感觉。2009年，我们确定了几个在肾脏中表达的ORs，包括这项提议的主题：Olfr90。我们最近解除了Olfr90的孤儿，并发现它能感知血液和尿液中存在的化学物质。然而，这些化学物质不是由宿主产生的--相反，它们是由真菌产生的代谢物。我们和其他人最近的研究表明，至少有三种细菌代谢物受体在调节宿主的生理参数方面发挥着重要作用；然而，很少有研究探讨真菌代谢物在脊椎动物生理中的作用。在这项建议中，我们将跟进这一有趣的发现，通过以下方式更好地了解Olfr90在肾脏中的作用： 确定Olfr90反应的配体及其生理相关性，(Ii)在肾脏内定位Olfr90，以及(Iii)检测Olfr90基因敲除小鼠在基线和暴露于真菌来源后的表型。我们在分子生物学、细胞生物学和肾脏生理学方面的丰富经验，包括先前的去变形ORs和研究宿主-微生物相互作用的工作，使我们非常适合探索这一令人兴奋的新领域。通过我们对这一新的信号通路的研究，我们希望扩大我们对宿主-微生物相互作用的理解，并揭示ORs在肾脏生理中的新作用。

 DESCRIPTION (provided by applicant): In recent years, olfactory receptors (ORs) have been shown to play a variety of important roles outside of the nose, acting as chemosensors to aid in muscle migration, sperm chemotaxis, and metabolite sensing. In 2009, we identified several ORs which are expressed in the kidney, including the topic of this proposal: Olfr90. We have recently deorphanized Olfr90, and found that it senses chemicals which have been reported to be present in blood and urine. However, these chemicals are not produced by the host - rather, they are metabolites produced by fungi. Recent studies by both our group and others have shown that there are at least three receptors for bacterial metabolites which play important roles in modulating physiological parameters in the host; however, few studies have examined a role for fungal metabolites in vertebrate physiology. In this proposal, we will follow up on this intriguing finding by working to better understand the role of Olfr90 in the kidney by: (I) Further characterizing the ligands to which Olfr90 responds and their physiological relevance, (II) Localizing Olfr90 within the kidney, and (III) Examining the phenotype of Olfr90 knockout mice both at baseline and after exposure to fungal sources. Our considerable experience in molecular biology, cell biology, and renal physiology, including previous work deorphanizing ORs and studying host-microbe interactions, makes us well-suited to explore this exciting new area. Through our studies of this novel signaling pathway, we hope to expand our understanding of host-microbe interactions and to uncover novel roles for ORs in renal physiology.