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

高血压中的短链脂肪酸 (SCFA) 和 SCFA G 蛋白偶联受体

基本信息

批准号：
10476066
负责人：
Jennifer L Pluznick
金额：
$ 10万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476066
关键词：
Acetates Address Affect Agreement Angiotensin II Binding Blood Pressure Blood Vessels Butyrates Carbon Conflict (Psychology)DOCA Data Disease Disease Outcome Disease Progression Dose FFAR3 gene Functional disorder Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Health Human Hypertension Infusion procedures Intervention Intestinal Absorption Intestines Juxtaglomerular Apparatus Kidney Knock-out Knockout Mice Ligands Literature Measures Modeling Mus Pathway interactions Phenotype Physiological Physiology Plasma Play Positioning Attribute Production Propionates Renal clearance function Renin Reporting Role Signal Pathway Sodium Chloride Sum Telemetry Testing Vascular Endothelium Volatile Fatty Acids base blood pressure regulation experimental study gut bacteria gut microbiota knockout animal microbial normotensive novel olfactory receptor public health relevance receptor receptor expression response trend

项目摘要

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.

项目概要肠道微生物群产生的代谢物在宿主生理学和我们之前已经证明了一类微生物代谢物，简称。链脂肪酸 (SCFA) 与宿主 G 蛋白偶联受体 (GPCR) 结合以调节血液我们发现 SCFA 会激活嗅觉受体 78 (Olfr78) 来调节肾素。最近，我们已经确定了另外两个。 GPCR（Gpr43 和 Olfr558）对 SCFA 做出反应并在脉管系统中表达，因此，我们也能很好地影响血压。在这项提案中，我们的目标是：研究 SCFA-GPCR 信号通路如何调节 – 以及如何被调节 – 在具体目标 1 中，我们将研究 SCFA 信号传导的组成部分。途径（SCFA 以及 SCFA GPCR）在两种不同的模型中进行调节高血压（血管紧张素 II 和 DOCA/盐）在高血压中增加；我们将测试我们的新假设，即改变宿主对 SCFA 的处理，而不是增加微生物生产是确定血浆水平的关键。为了实现这一目标，我们将测量微生物。正常血压和两种情况下 SCFA 的产生、肠道重吸收和肾脏清除为了检查高血压中的 SCFA GPCR，我们将确定如何 Olfr78、Olfr558、Gpr41 和 Gpr43 的表达在正常血压与在该提案的具体目标 2 中，我们将确定其中每一个如何。 SCFA-GPCR 信号通路的成分可以调节高血压的病程。过去我们主要研究了 Olfr78 和 Gpr41，因此，我们将重点研究揭示 Olfr558 和 Gpr43 在基础血压调节中的新作用在一个单独的实验中，我们将测试我们的新假设：低剂量的 SCFA 具有保护作用，但较高剂量的 SCFA 会产生疼痛，因此解决文献中的冲突为此，我们将治疗正常血压和高血压。小鼠接受不同剂量的外源 SCFA 总而言之，这些研究将推动该领域的发展。阐明 SCFA 和 SCFA GPCR 在高血压中的调节方式，并通过确定调节该途径如何改变高血压的病程。