Uncovering the Functional Role of Olfr78 in Blood Pressure Regulation

揭示 Olfr78 在血压调节中的功能作用

基本信息

批准号：
9007953
负责人：
Jennifer L Pluznick
金额：
$ 36.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9007953
关键词：
Acute Animals Antihypertensive Agents Biological Assay Blood Pressure Blood Vessels Cells Chemicals Chemoreceptors Clinical Coupled Data Ensure Future GTP-Binding Proteins Genetic Goals Human Hypotension In Vitro Juxtaglomerular Apparatus Juxtaglomerular Cell Kidney Knock-out Knockout Mice Lead Ligands Mediating Metabolism Mus Nose Orthologous Gene Pathway interactions Peripheral Phenotype Physiological Physiology Play Publishing Renal function Renin Reporting Role Signal Transduction Site Smell Perception Smooth Muscle Myocytes Sum System Techniques Testing Tissues Vascular Smooth Muscle Volatile Fatty Acids Wild Type Mouse Work base blood pressure reduction blood pressure regulation cell type detector gut microbiota in vivo microbial mouse model novel olfactory receptor public health relevance receptor recombinase-mediated cassette exchange response tool vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Recent studies have demonstrated that Olfactory Receptors (ORs) play important physiological roles as chemosensors in tissues beyond the nose. We have reported that one of the ORs expressed in the kidney, Olfactory Receptor 78 (Olfr78), plays an important role in blood pressure (BP) regulation. Intriguingly, the ligands for this receptor are short chain fatty acids (SCFAs), which are metabolites produced by the gut microbiota. The key role of Olfr78 in modulating BP is clearly demonstrated by the hypotension (~13mmHg) observed in mice null for Olfr78 (Olfr78 KO). However, Olfr78 localizes to multiple tissues that influence BP regulation - it is not only found in the renal juxtaglomerular apparatus (JGA), which plays a role in renin secretion, but it is also expressed in the peripheral vasculature, where it appears to modulate vascular tone. In this proposal, we will utilize the flox cre system to determine which site of Olfr78 expression is the primary contributor to the hypotension seen in the KO mice (SA1). In addition, because Olfr78 KO mice are hypotensive, we hypothesize that an Olfr78 antagonist would likewise lower BP and would be an extremely useful tool for teasing apart the role of Olfr78 in BP regulation in vivo. Therefore, in SA2, we wil carry out in vitro studies to characterize Olfr78 antagonists (building upon our strong preliminary data), and will determine which compounds are the best candidates for in vivo use. In SA3, we will utilize Olfr78 antagonists in vivo in both wild-type and various KO mice in order to advance our understanding of Olfr78 function. In sum, our data implies that a novel renal OR plays a role in modulating BP regulation in response to changes in gut microbial metabolism. The proposed work invokes a variety of in vitro and in vivo techniques in order to advance our understanding of BP regulation by studying an entirely novel pathway involving a novel renal OR. These studies have the potential to lead to potentially exciting future clinical implications, as our dat suggests that manipulating Olfr78 in vivo has the potential to significantly alter BP.

描述（由适用提供）：最近的研究表明，嗅觉受体（ORS）在鼻子以外的组织中起重要的物理作用。我们报告说，在肾脏嗅觉受体78（OLFR78）中表达的OR在血压调节（BP）调节中起重要作用。有趣的是，该受体的配体是短链脂肪酸（SCFA），这是肠道菌群产生的代谢产物。 OLFR78（OLFR78 KO）中观察到的低血压（〜13mmHg）清楚地证明了OLFR78在调节BP中的关键作用。但是，OLFR78本地化在影响BP调节的多个时机上 - 它不仅在肾近胶体设备（JGA）中发现，在肾素分泌中起作用，而且在外围脉管系统中也表达了它，在那里似乎调节了血管张力。在此提案中，我们将利用Flox 确定哪种OLFR78表达位点的CRE系统是促进KO小鼠（SA1）中低血压的主要因素。此外，由于OLFR78 KO小鼠是降压性的，因此我们假设OLFR78拮抗剂同样会降低BP，并且是嘲笑OLFR78在体内BP调节中的作用的非常有用的工具。因此，在SA2中，我们将进行体外研究，以表征OLFR78拮抗剂（建筑物）。在我们强大的初步数据），并将确定哪些化合物是体内使用的最佳候选物。在SA3中，我们将在野生型和各种KO小鼠的体内使用OLFR78拮抗剂，以促进我们对OLFR78功能的理解。总而言之，我们的数据意味着新颖的肾脏或在调节肠道微生物代谢变化的响应中调节BP调节中起作用。提出的工作调用了各种体外和体内技术，以通过研究涉及新型肾脏或新颖的途径来提高我们对BP调节的理解。这些研究有可能导致潜在的未来临床意义，因为我们的DAT表明，在体内操纵OLFR78有可能显着改变BP。