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.

项目摘要肠道菌群产生的代谢产物在宿主生理和病理生理学。我们以前已经表明，一类微生物代谢产物，短链脂肪酸（SCFA），与宿主G蛋白偶联受体（GPCR）结合以调节血液压力。我们发现SCFA激活嗅觉受体78（OLFR78）调节肾素释放，并激活GPR41以调节血管张力。最近，我们确定了另外两个对SCFA响应并在脉管系统中表达的GPCR（GPR43和OLFR558），因此，也有充分的位置，也会影响血压。在此提案中，我们的目标是研究SCFA-GPCR信号通路如何调节 - 由 - 调制 - 高血压。在特定目标1中，我们将研究SCFA信号的组件如何途径（SCFA，以及SCFA GPCR）在两个不同的模型中调制高血压（血管紧张素II和DOCA/盐）。血浆SCFA的高血压增加；这里，我们将测试我们的新假设，该假设改变了SCFA的宿主处理，而不会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 SCFA的生产，肠重吸收和肾脏清除率正常高血压模型。为了检查高血压中的SCFA GPCR，我们将确定 OLFR78，OLFR558，GPR41和GPR43的表达发生了变化高血压。在本提案的特定目的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病程。过去，我们已经广泛研究了OLFR78和GPR41，因此，我们将重点放在在基本的血压调节中发现OLFR558和GPR43的新作用疾病和高血压。在另一个实验中，我们将测试我们的新假设低剂量的SCFA受到保护，但较高剂量的SCFA是有害的，从而解决文学中的冲突。为此，我们将治疗正常的和高血压具有不同剂量的外源SCFA的小鼠。总而言之，这些研究将通过阐明SCFA和SCFA GPCR在高血压中如何调节，并确定该途径的调节如何改变高血压的过程。