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: 7666211
• 负责人: Jennifer L Pluznick
• 金额: $ 8.84万
• 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/7666211
• 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; 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; 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; public health relevance; 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）是七次跨膜化学传感器，负责嗅觉上皮中气味检测的第一步。最近，OR 也被发现在非嗅觉组织的化学感觉中发挥作用。然而，OR 作为肾脏中化学传感器的作用，以及因此作为肾功能的潜在调节剂的作用，此前尚未被研究过。初步数据表明，各个 OR 以及嗅觉必需的下游信号成分（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，嗅觉形式腺苷酸环化酶缺陷的小鼠无法正确调节肾小球滤过率——我们认为这种缺陷是由于肾小球反馈调节不当造成的。在本提案中，我们将：(1) 定位肾脏内的 OR，(2) 确定嗅觉机制是否在肾小管肾小球反馈中发挥作用，以及 (3) 确定肾脏 OR 在体外和体内检测到的配体。该候选人的目标集中在了解肾脏生理学和病理生理学，她打算从事研究方面的学术任命。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，申办者实验室为研究新型肾脏信号通路提供了绝佳的环境。 公众健康相关性：肾功能最重要的方面之一是肾脏正确调节和调整尿流量和尿流量以及监测尿液各种成分的能力；然而，这一过程的细节尚不完全清楚。我们发现，鼻子中让您闻到气味的蛋白质也存在于负责监测尿流的肾脏细胞中。在这项提案中，我们将研究这些蛋白质如何帮助肾脏在尿液流过时“嗅探”尿液，以便仔细监测和调整尿液的量、速率和各种成分。