Olfactory Proteins in the Kidney and Regulation of Glomerular Filtration Rate

描述(由申请人提供)： 嗅觉受体(ORs)是七种跨膜化学传感器，负责嗅觉上皮气味检测的初始步骤。最近，ORs也被发现在非嗅觉组织的化学感觉中发挥作用。然而，ORs在肾脏中作为化学感受器的作用，因此作为肾功能的潜在调节因子，以前还没有被研究过。初步数据表明，单个ORs以及嗅觉所必需的下游信号成分(嗅觉G蛋白和嗅觉形式的腺苷环化酶)在肾脏中表达。此外，缺乏嗅觉形式的腺苷环化酶的小鼠不能适当地调节肾小球滤过的速率--我们认为这种缺陷是由于对管球反馈的不适当调节所致。在这个方案中，我们将：(1)将ORs定位在肾脏内；(2)确定嗅觉机制是否在肾小球反馈中起作用；(3)确定肾ORs在体外和体内检测到的配体(S)。这位候选人的目标是了解肾脏生理学和病理生理学，她打算在研究方面寻求学术任命。耶鲁大学细胞和分子生理学系是进一步培养候选人对肾脏生理学的兴趣和专业知识的理想环境，赞助商的实验室为研究新的肾脏信号通路提供了极好的环境。

DESCRIPTION (provided by applicant): Olfactory receptors (ORs) are seven-transmembrane chemosensors which are responsible for the initial step of odorant detection in the olfactory epithelium. Recently, ORs have also been found to play a role in chemosensation in non-olfactory tissues. However, a role of ORs as chemosensors in the kidney, and therefore as potential regulators of kidney function, has not previously been investigated. Preliminary data demonstrates that individual ORs, as well as the necessary downstream signaling components of olfaction (the olfactory G protein and the olfactory form of adenylate cyclase) are expressed in the kidney. Furthermore, a mouse deficient for the olfactory form of adenylate cyclase is unable to properly regulate the rate of glomerular filtration - a deficit we believe is due to inappropriate regulation of tubuloglomerular feedback. In this proposal, we will: (1) Localize ORs within the kidney, (2) Determine if the olfaction machinery plays a role in tubuloglomerular feedback, and (3) Determine the ligand(s) detected by renal ORs in vitro and in vivo. The candidate's goals are focused on understanding renal physiology and pathophysiology, and she intends to pursue an academic appointment in research. The Department of Cellular and Molecular Physiology at Yale University is an ideal environment in which to further cultivate the candidate's interest and expertise in renal physiology, and the Sponsor's Laboratory provides an excellent setting in which to investigate a novel renal signaling pathway.