Renal Olfactory Receptor 1393: Ligands, Localization and Function

描述(申请人提供)：嗅觉受体(ORs)是七种跨膜区G蛋白偶联的化学感受器，在鼻子中充当嗅觉传感器。最近的研究发现，ORs和其他化学感受器也在其天然组织外表达，包括在精子、肌肉和脊柱中，它们在这些组织中具有重要的功能作用。我们之前已经报道过OR信号也在肾脏中发挥作用，并且正在积极地表征单个肾脏OR的生理功能。到目前为止，我们已经确定了9个肾脏OR，其中包括这项提案的主题Olfr1393。初步研究结果表明，Olfr1393仅定位于近端小管(S1、S2和S3段)。近端小管始于肾小球底部，延伸至Henle环，是肾单位与新形成的尿液接触的第一段。因此，近端小管具有活跃的转运速度，并负责大多数肾脏溶质的重吸收，包括盐、水、钾、葡萄糖和氨基酸。在这项提案中，我们旨在通过提出三个主要问题来了解Olfr1393在近端小管中所起的作用。首先，Olfr1393的配体(S)是什么？第二，Olfr1393的完整表达模式是什么？最后，Olfr1393及其配体在肾脏中起什么作用？我们在分子生物学、细胞生物学和肾脏生理学领域的丰富经验使我们有条件进行这些令人兴奋的实验。通过揭示这一新的信号通路在近端小管和整个肾脏功能中的作用，我们希望揭示ORs的新角色，并更好地理解肾脏如何维持对内环境平衡功能的如此严格的调节。

DESCRIPTION (provided by applicant): Olfactory receptors (ORs) are seven transmembrane domain G protein-coupled chemosensory receptors that serve as sensors of smell in the nose. Recently, studies have found that ORs and other chemosensors are also expressed outside of their native tissues, including in sperm, muscle and the spinal column, where they have important functional roles. We have previously reported that OR signaling also plays a role in the kidney and are actively characterizing the physiological functions of individual renal ORs. To date, we have identified 9 renal ORs including Olfr1393 which is the subject of this proposal. Preliminary findings suggest that Olfr1393 is exclusively localized to the proximal tubule (segments S1, S2 and S3). The proximal tubule begins at the base of the glomerulus and extends to the Loop of Henle, thus, it is the first segment of the nephron to come in contact with the newly forming urine. Therefore, the proximal tubule has an active rate of transport and is responsible for the majority of renal solute reabsorption including salt, water, potassium, glucose and amino acids. In this proposal, we aim to understand the role that Olfr1393 plays in the proximal tubule by asking three major questions. First, what is the ligand(s) for Olfr1393? Second, what is the complete expression pattern of Olfr1393? Finally, what functional role does Olfr1393 and its ligand play in the kidney? Our considerable experience in the field of molecular biology, cell biology and renal physiology well-situates us to perform these exciting experiments. By uncovering the role of this novel signaling pathway in the proximal tubule and in renal function as a whole, we hope to uncover novel roles for ORs and better understand how the kidney maintains such tight regulation on homeostatic functions.