Short Chain Fatty Acids (SCFAs) and SCFA G-protein Coupled Receptors in Hypertension

项目摘要 肠道微生物区系产生的代谢物在寄主生理和 病理生理学。我们之前已经证明了一类微生物代谢物，Short 链脂肪酸(SCFA)，结合宿主G蛋白偶联受体(GPCRs)调节血液 压力。我们发现SCFA激活嗅觉受体78(Olfr78)来调节肾素 释放并激活Gpr41来调节血管张力。最近，我们又确认了另外两名 GPCRs(Gpr43和Olfr558)对SCFA作出反应并在血管系统中表达， 因此，它们处于有利地位，也可以影响血压。在这项建议中，我们的目标是 研究SCFA-GPCR信号通路如何调节-以及被调节- 高血压。在特定的目标1中，我们将检查SCFA信令的组件是如何 途径(SCFA以及SCFA GPCRs)在两种不同的模型中被调制 高血压(血管紧张素II和DOCA/盐)。高血压患者血浆SCFAs升高；在这里， 我们将测试我们的新假设，即改变了宿主对SCFA的处理，而不是增加了微生物 生产，是决定血浆水平的关键。为了实现这一点，我们将测量微生物 在正常血压和两种情况下SCFAs的产生、肠道重吸收和肾清除 高血压模型。为了研究高血压患者的SCFA GPCR，我们将确定 Olfr78、Olfr558、Gpr41和Gpr43的表达在正常血压与 高血压。在本提案的具体目标2中，我们将确定其中的每一个 SCFA-GPCR信号通路的组成部分可以调节高血压的病程。 我们过去对Olfr78和Gpr41进行了广泛的研究，因此，我们将重点关注 揭示Olfr558和Gpr43在基础血压调节中的新作用 条件和高血压。在另一个单独的实验中，我们将测试我们的新假设 低剂量的单链脂肪酸是保护的，但高剂量的单链脂肪酸是有害的，因此 解决文学作品中的冲突。为了做到这一点，我们将治疗血压正常和高血压 不同剂量的外源性单链脂肪酸对小鼠的影响。总而言之，这些研究将推动该领域的发展 阐明SCFA和SCFA GPCRs在高血压中是如何调节的，并通过确定 这一途径的调节如何改变高血压的进程。

Project Summary Metabolites produced by the gut microbiota play critical roles in host physiology and pathophysiology. We have previously shown that one class of microbial metabolites, short chain fatty acids (SCFAs), bind to host G protein-coupled receptors (GPCRs) to modulate blood pressure. We have found that SCFAs activate Olfactory Receptor 78 (Olfr78) to modulate renin release, and activate Gpr41 to modulate vascular tone. Recently, we have identified two other GPCRs (Gpr43 and Olfr558) which respond to SCFAs and are expressed in the vasculature, and thus are well-positioned to also influence blood pressure. In this proposal, we Aim to investigate how SCFA-GPCR signaling pathways modulate – and are modulated by – hypertension. In Specific Aim 1, we will examine how components of the SCFA signaling pathway (SCFAs, as well as SCFA GPCRs) are modulated in two different models of hypertension (Angiotensin II, and DOCA/Salt). Plasma SCFAs increase in hypertension; here, we will test our novel hypothesis that altered host handling of SCFAs, not increased microbial production, is key in determining plasma levels. To achieve this, we will measure microbial production, intestinal reabsorption, and renal clearance of SCFAs in normotension and in two hypertension models. To examine SCFA GPCRs in hypertension, we will determine how the expression of Olfr78, Olfr558, Gpr41, and Gpr43 is altered in normotension versus hypertension. In Specific Aim 2 of this proposal, we will determine how each of these components of the SCFA-GPCR signaling pathway can modulate the course of hypertension. We have extensively studied Olfr78 and Gpr41 in the past, therefore, we will focus on uncovering novel roles for Olfr558 and Gpr43 in blood pressure regulation under basal conditions and in hypertension. In a separate experiment, we will test our novel hypothesis that low doses of SCFAs are protective but higher doses of SCFAs are detrimental, thereby resolving a conflict in the literature. To do this, we will treat normotensive and hypertensive mice with varying doses of exogenous SCFAs. In sum, these studies will advance the field by illuminating how SCFAs and SCFA GPCRs are modulated in hypertension, and by determining how modulation of this pathway can alter the course of hypertension.