Elucidating the Role of Olfactory Receptor 1393 in Renal Glucose Handling

项目摘要 嗅觉受体(ORs)是7种跨膜区G蛋白偶联的化学感觉受体。 在鼻子里起到嗅觉的作用。最近，研究发现，ORS和其他化学传感器是 也在天然组织之外表达，包括在精子、肌肉和脊柱中，在那里它们 具有重要的职能作用。我们之前已经报道过OR信号在肾脏中也起作用 最近发现了其中一个受体Olfr1393，发现于人牙髓细胞顶端质膜上。 近端小管。Olfr1393基因敲除(KO)小鼠出现正常血糖尿和血糖改善 宽容。因此，看起来Olfr1393在肾脏葡萄糖处理中起作用。葡萄糖被自由过滤 肾小球，几乎100%的肾小球从近端小管的管腔中被两个 钠-葡萄糖共转运蛋白SGLT1和SGLT2。这些转运蛋白处理所有的葡萄糖重吸收，它是 通常情况下，只有在高血糖时期，尿液中才会出现葡萄糖。与以下功能保持一致 在葡萄糖处理中，我们发现Olfr1393中SGLT1的管腔染色减少了22% KO小鼠，但SGLT2无变化。因此，我们认为Olfr1393是一种新的肾脏SGLT1的调节因子。 近端小管。在这项提案中，我们的目标是通过研究Olfr1393的 能够影响SGLT1的定位、表达或活性。此外，我们将在上下文中研究Olfr1393 已知的唯一另一种SGLT1的基本调节因子RS1。最后，我们还在调查Olfr1393信号是如何 在糖尿病进展中的作用，以及调制是否可以降低血糖。为了做到这一点，我们 会诱发Olfr1393野生型和KO小鼠糖尿病，并观察它们的血糖、血糖升高情况 耐受性、肾小球滤过率与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和肾脏转运蛋白的调节，这项建议将完成 在经验丰富的导师团队的指导下，该团队包括有经验的肾脏生理学家和 新陈代谢研究人员。为了实现这一点，应聘者将与她的导师和专业人员合作 发展办公室遵循职业发展计划，包括手稿准备、参加和 出席国际会议和院系研讨会，指导研究生和本科生 学生，并准备申请材料。

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.