Uncovering the Functional Role of Olfr78 in Blood Pressure Regulation

 描述(申请人提供)：最近的研究表明，嗅觉受体(ORs)在鼻子以外的组织中作为化学传感器发挥着重要的生理作用。我们已经报道，在肾脏中表达的ORs之一，嗅觉受体78(Olfr78)，在血压调节中起着重要作用。有趣的是，这种受体的配体是短链脂肪酸(SCFAs)，它是肠道微生物区系产生的代谢物。Olfr78在调节血压中的关键作用在小鼠体内观察到的低血压(~13毫米汞)清楚地证明了Olfr78的零(Olfr78 KO)。然而，Olfr78定位于影响血压调节的多个组织-它不仅存在于肾小球旁装置(JGA)，它在肾素分泌中发挥作用，而且它也在外周血管系统中表达，在那里它似乎调节血管张力。在本提案中，我们将使用FLOX Cre系统，以确定Olfr78表达的哪个位点是导致KO小鼠低血压的主要因素(SA1)。此外，因为Olfr78 KO小鼠是低血压的，我们假设Olfr78拮抗剂同样会降低血压，并且将是一个极其有用的工具来梳理Olfr78在体内BP调节中的作用。因此，在SA2中，我们将进行体外研究，以表征Olfr78拮抗剂(建立在我们强大的初步基础上 数据)，并将确定哪些化合物是体内使用的最佳候选化合物。在SA3中，我们将在野生型和各种KO小鼠体内使用Olfr78拮抗剂，以促进我们对Olfr78功能的理解。总之，我们的数据表明，一种新的肾脏OR在调节血压调节方面发挥了作用，以响应肠道微生物代谢的变化。这项拟议的工作引用了各种体外和体内技术，以通过研究一种涉及新的肾脏OR的全新途径来促进我们对BP调节的理解。这些研究有可能导致潜在的令人兴奋的未来临床意义，因为我们的DAT表明，在体内操纵Olfr78有可能显著改变BP。

 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.