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Elucidating the Role of Olfactory Receptor 1393 in Renal Glucose Handling

阐明嗅觉受体 1393 在肾葡萄糖处理中的作用

基本信息

批准号：
10440017
负责人：
Blythe D Shepard
金额：
$ 4.93万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-29 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440017
关键词：
Affect Apical Blood Glucose Blood Vessels Bolus Infusion Cell membrane Chemicals Clinical Complications of Diabetes Mellitus Coupled Defect Development Development Plans Diabetes Mellitus Disease Disease model Epidemic Exhibits GTP-Binding Proteins Glomerular Filtration Rate Glucose Glucose tolerance test Glycosuria Goals Health Human Hyperglycemia Impairment In Vitro Injury to Kidney International Kidney Kidney Glomerulus Knock-out Knockout Mice Knowledge Lead Manuscripts Mediating Mentors Metabolic Mus Muscle Neuropathy Non-Insulin-Dependent Diabetes Mellitus Nose Olfactory Epithelium Organ Oxidative Stress Pathway interactions Patients Pharmacology Phenotype Physiology Plasma Play Preparation Proximal Kidney Tubules Receptor Signaling Regulation Reporting Research Personnel Resistance Role Signal Pathway Signal Transduction Smell Perception Sodium Stains Taste Buds Testing Therapeutic Therapeutic Agents Tissues Transmembrane Domain Urine Vascular Diseases Vertebral column Work blood glucose regulation career development cell type diabetic experience glucose tolerance glucose uptake graduate student improved in vivo interest new therapeutic target novel novel therapeutics olfactory receptor receptor sensor sperm cell symporter symposium therapeutic target therapeutically effective trafficking type I and type II diabetes undergraduate student uptake urinary wasting

项目摘要

Project Summary 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 recently found one of these receptors, Olfr1393, to be found on the apical plasma membrane of the proximal tubule. Olfr1393 knockout (KO) mice present with euglycemic glycosuria and improved glucose tolerance. Thus, it appears that Olfr1393 plays a role in renal glucose handling. Glucose is freely filtered by the renal glomerulus, and nearly 100% of it is reabsorbed from the lumen of the proximal tubule by two sodium-glucose co-transporters, Sglt1 and Sglt2. These transporters handle all glucose reabsorption, and it is typically only during periods of hyperglycemia that glucose appears in the urine. In keeping with a function for Olfr1393 in glucose handling, we found that there is a 22% decrease in the luminal staining of Sglt1 in Olfr1393 KO mice, but no change in Sglt2. Thus, we propose that Olfr1393 is a novel regulator for Sglt1 in the renal proximal tubule. In this proposal, we are aiming to understand how Olfr1393 regulates Sglt1 by examining its ability to influence Sglt1 localization, expression or activity. In addition, we will examine Olfr1393 in the context of the only other known basal regulator of Sglt1, RS1. Finally, we are also investigating how Olfr1393 signaling functions in the progression of diabetes, and whether modulation can lower plasma glucose. To do that, we will induce diabetes in Olfr1393 wild type and KO mice and investigate their rise in plasma glucose, glucose tolerance, glomerular filtration rate and progression of neuropathy and vascular disease. The candidate's goals are to understand renal physiology and renal transporter regulation, and this proposal will be completed under the guidance of an experienced mentor team that includes accomplished renal physiologists and metabolic researchers. To accomplish this, the candidate will work with her mentors and the Professional Development Office to follow a career development plan that includes manuscript preparation, attending and presenting at international conferences and departmental seminars, mentoring of graduate and undergraduate students, and preparation of application materials.

项目摘要嗅觉受体（ORs）是七个跨膜结构域G蛋白偶联的化学感受受体，作为鼻子的嗅觉传感器。最近，研究发现OR和其他化学传感器是也在其天然组织外表达，包括精子、肌肉和脊柱，具有重要的功能作用。我们以前曾报道过OR信号在肾脏中也起作用最近发现这些受体之一，Olfr 1393，被发现在顶端质膜上，近端小管Olfr 1393敲除（KO）小鼠出现正常血糖糖尿和葡萄糖改善宽容因此，Olfr 1393似乎在肾脏葡萄糖处理中起作用。葡萄糖被自由过滤，肾小球，并且几乎100%的它被两个细胞从近端小管的管腔重吸收。钠-葡萄糖共转运蛋白Sglt 1和Sglt 2。这些转运蛋白处理所有的葡萄糖重吸收，通常仅在高血糖期间葡萄糖出现在尿中。为了与一个函数保持一致， Olfr 1393在葡萄糖处理中，我们发现Olfr 1393中Sglt 1的管腔染色减少了22 KO小鼠，但Sglt 2无变化。因此，我们认为Olfr 1393是肾脏中Sglt 1的一种新的调节剂。近端小管在这项提案中，我们的目标是通过检查Olfr 1393对Sglt 1的调节，了解Olfr 1393是如何调节Sglt 1的。影响Sglt 1定位、表达或活性的能力。此外，我们将在以下背景下检查Olfr 1393 另一个已知的Sglt 1基础调节因子RS 1。最后，我们还研究了Olfr 1393信号传导如何影响细胞的增殖。在糖尿病进展中的作用，以及调节是否可以降低血糖。为此我们将在Olfr 1393野生型和KO小鼠中诱导糖尿病，并研究它们的血浆葡萄糖、葡萄糖代谢和血糖水平的升高。耐受性、肾小球滤过率以及神经病变和血管疾病的进展。候选人的目标是了解肾脏生理学和肾脏转运蛋白调节，本提案将完成在经验丰富的导师团队的指导下，包括有成就的肾脏生理学家和代谢研究者要做到这一点，候选人将与她的导师和专业发展办公室遵循职业发展计划，包括手稿准备，出席和出席国际会议和部门研讨会，指导研究生和本科生学生，并准备申请材料。