Olfactory Proteins in the Kidney and Regulation of Glomerular Filtration Rate

肾脏中的嗅觉蛋白与肾小球滤过率的调节

• 批准号: 7512189
• 负责人: Jennifer L Pluznick
• 金额: $ 8.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-28 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512189
• 关键词: Adenylate Cyclase; Animals; Anosmia; Antibodies; Appointment; Bardet-Biedl Syndrome; Binding; Biological Assay; Cells; Chemicals; Chronic; Complement; Custom; Cystic kidney; Data; Detection; Disease; Distal; Environment; Exhibits; Feedback; Flow-It; Functional disorder; GTP-Binding Proteins; Glomerular Filtration Rate; Goals; Homeostasis; In Situ; In Situ Hybridization; In Vitro; Individual; Kidney; Knock-out; Knockout Mice; Laboratories; Length; Ligands; Localized; Macula densa; Measures; Micropuncture; Molecular; Monitor; Mus; Nephrons; Nifedipine; Nose; Olfactory Epithelium; Olfactory Pathways; Oocytes; Patients; Phenotype; Physiological; Physiology; Plasma; Play; Process; Property; Protein Isoforms; Proteins; Public Health; Rate; Regulation; Renal Tissue; Renal function; Renin; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Signal Pathway; Signal Transduction; Smell Perception; Testing; Tissues; Universities; Up-Regulation; Urine; Work; Xenopus laevis; arteriole; base; design; in vitro Assay; in vivo; indexing; interest; laser capture microdissection; novel; olfactory receptor; receptor; receptor binding; receptor coupling; research study; response; vasoconstriction

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. PUBLIC HEALTH RELEVANCE: One of the most important aspects of kidney function is the kidney's ability to properly regulate and adjust the amount and rate of urine flow as well as to monitor the various components of urine; however, the details of this process are not fully understood. We have found that the same proteins in your nose which allow you to smell are also present in the cells in your kidney which are responsible for monitoring urine flow. In this proposal, we will investigate how these proteins help the kidney to "sniff" the urine as it flows by so that the amount, rate, and various components of urine can be carefully monitored and adjusted.

描述（由申请人提供）： 嗅觉受体（OR）是七跨膜化学传感器，是嗅觉上皮中气味检测的第一步。最近，还发现ORS在非富尔科组织的化学一致化中发挥作用。然而，以前尚未研究ORS作为化学传感器在肾脏中的作用，因此是肾功能的潜在调节剂。初步数据表明，单个ORS以及嗅觉的必要下游信号传导成分（嗅觉G蛋白和腺苷酸环化酶的嗅觉形式）在肾脏中表达。此外，缺乏腺苷酸环化酶嗅觉形式的小鼠无法正确调节肾小球滤过的速率 - 我们认为赤字是由于微管粒反馈的不适当调节所致。在此提案中，我们将：（1）将OR定位在肾脏中，（2）确定嗅觉机械是否在肾小管反馈中起作用，并且（3）确定由体外和体内肾ORS检测到的配体（S）。候选人的目标集中在理解肾脏生理学和病理生理学上，她打算在研究中进行学术任命。耶鲁大学的细胞和分子生理学系是一个理想的环境，在该环境中，旨在进一步培养候选人在肾脏生理学方面的兴趣和专业知识，并且赞助商的实验室提供了一个很好的环境，可以在其中研究一种新型的肾脏信号通路。 公共卫生相关性：肾功能的最重要方面之一是肾脏能够正确调节和调整尿液流量和速率以及监测尿液的各种成分的能力；但是，此过程的细节尚未完全理解。我们发现，您的鼻子中相同的蛋白质使您闻到的肾脏也存在于肾脏的细胞中，这些蛋白质负责监测尿液。在此提案中，我们将研究这些蛋白质如何帮助肾脏流动时“嗅探”尿液，以便可以仔细监测和调整尿液的量，速率和各种成分。