Identification of mechano versus chemo-sensitive renal sensory neurons in hypertension

高血压中机械敏感肾感觉神经元与化学敏感肾感觉神经元的鉴定

基本信息

批准号：
10593129
负责人：
SEAN D STOCKER
金额：
$ 59.81万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593129
关键词：
Acute Afferent Neurons Anatomy Antihypertensive Agents Attenuated Blood Pressure Cardiovascular system Cations Cells Chemicals Chronic Clinical Trials Data Denervation Disease Drug resistance Excision Experimental Animal Model Fiber Future Genes Genetic Goals Guidelines Hypertension Individual Ion Channel Kidney Knowledge Laboratories Lead Link Maps Mechanics Mediating Modeling Mus Nerve Nerve Fibers Neural Pathways Neuroanatomy Neurons Pathologic Pelvis Perfusion Phenotype Piezo 2 ion channel Population Regulation Renal Mass Renal function Renin Renovascular Hypertension Role Sensory Site Sodium Stenosis Stimulus TRPV1 gene Temperature Testing Time Tracer Vanilloid Viral absorption afferent nerve experimental study hemodynamics hypertension treatment hypertensive in vivo kidney vascular structure nerve supply neurochemistry neuromechanism novel therapeutic intervention optogenetics pressure receptor response targeted treatment transcriptomics

项目摘要

ABSTRACT Renal denervation lowers arterial blood pressure in multiple clinical trials and experimental animal models of hypertension. These anti-hypertensive effects have been partly attributed to the removal of renal sensory nerves as selective denervation of renal sensory nerves lowers arterial blood pressure to the same extent as total renal denervation. Despite our current knowledge of renal nerves, there is a severe lack of anatomical, functional, and mechanistic knowledge about the specific sensory fiber-types responsible for cardiovascular control. Renal sensory nerves detect mechanical and chemical stimuli within the kidneys and consequently alter sodium reabsorption, renin secretion, and sympathetic outflow. These responses are dependent on mechano- and chemo- sensitive nerve fibers which have not been clearly defined. Our preliminary data using single-cell transcriptomics on renal sensory neurons demonstrates the existence of two distinct populations: the mechanosensitive channel Piezo2 and chemosensitive channel TRPV1. The overall hypothesis of this proposal is that neurochemically distinct populations of renal sensory neurons expressing Piezo2 and TRPV1 mediate mechano- and chemo-sensitive responses in the kidney. The neurochemical profile of these neurons switches in renal stenosis from a loss of Piezo2-mechanosensitive fibers to robust expression and increased sensitivity of TRPV1-chemosensitive fibers to elevated sympathetic outflow and arterial blood pressure. Aim 1 will employ in vivo single-unit recordings, single-cell transcriptomics (>40 sensory genes), and optogenetics to determine the extent by which Piezo2 and TRPV1-expressing neurons represent mechano- and chemo- sensitive renal sensory nerve populations. Aim 2 will determine how hypertension produced by renal stenosis alters the mechano- versus chemosensitivity of renal afferents, the neurochemical profile of sensory neurons, and the sensory innervation of the kidney. Aim 3 will directly assess the contribution of Piezo2 versus TRPV1 renal sensory fibers and channels to renal sensory function and renovascular hypertension. This proposal will define, for the first time, the neurochemical and functional phenotype of renal sensory nerve populations involved in the control of arterial blood pressure, anatomically map innervation sites in the kidney, and functionally test distinct renal afferent fibers populations and channels in vivo that have a pathological role of hypertension.

抽象的肾脏去神经可在多个临床试验和实验动物中降低动脉血压高血压模型。这些抗高血压作用部分归因于去除肾脏感觉神经作为肾脏感觉神经的选择性神经降低动脉血压的程度与总肾脏神经相同。尽管我们目前了解肾神经，严重缺乏有关有关的解剖学，功能和机械知识负责心血管控制的特定感觉纤维类型。肾脏感觉神经检测肾脏内的机械和化学刺激，因此改变了钠重吸收，肾素分泌和交感神经流出。这些响应取决于尚未明确定义的机械和化学敏感神经纤维。我们的初步在肾脏感觉神经元上使用单细胞转录组学的数据证明了存在两个不同的人群：机械敏感的通道压电和化学敏感通道 TRPV1。该提议的总体假设是神经化学上不同的人群表达压电和TRPV1的肾脏感觉神经元介导机械和化学敏感的肾脏的反应。这些神经元切换的神经化学特征在肾狭窄中开关从压电敏感纤维的损失到稳健的表达和提高的灵敏度 TRPV1化学敏感纤维可升高交感神经流出和动脉血压。目标1 将使用体内单单元记录，单细胞转录组学（> 40个感觉基因）和光遗传学以确定表达压电2和TRPV1的神经元的程度机械和化学敏感的肾脏感觉神经种群。 AIM 2将决定如何肾脏狭窄产生的高血压改变了肾脏的机械与化学敏感性传入，感觉神经元的神经化学谱以及感官神经肾。 AIM 3将直接评估压电2与TRPV1肾脏感觉纤维的贡献和肾脏感觉功能和肾血管高血压的通道。该建议将定义第一次，肾脏感觉神经群的神经化学和功能表型参与控制动脉血压的控制，解剖学映射肾脏的神经支配部位，并在功能上测试具有一个具有的不同肾脏传入纤维种群和频道的体内高血压的病理作用。