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Role played by Acid Ion Sensing Channels in Peripheral Artery Disease

酸离子传感通道在外周动脉疾病中的作用

基本信息

批准号：
10531228
负责人：
Marc Peter Kaufman
金额：
$ 58.11万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
2020-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531228
关键词：
ASIC channel Acids Animal Disease Models Animal Model Arrhythmia Arteries Attention Attenuated Blood Vessels Blood flow Brain Stem CRISPR/Cas technology Cardiac Cardiovascular system Chest Pain Contracts Coronary artery Decerebration procedure Disease Epidemiology Exercise Fiber Generations Goals Health Heart Heart Contractilities Heart Rate Hindlimb Hour Hydrogen-Ion Concentration Individual Intermittent Claudication Ischemia Kidney Knock-out Lactic acid Leg Legal patent Life Ligation Limb structure Metabolic Muscle Muscle Contraction Muscle Form Glycogen Phosphorylase Myocardial Myocardial Infarction Names Nerve Oxygen Pain Patients Pattern Perfusion Peripheral Peripheral arterial disease Play Preparation Production Protein Isoforms Rattus Reflex action Role Signal Transduction Skeletal Muscle Small Interfering RNA Spinal Cord Stimulus Stroke Sympathetic Nervous System Technology Testing Thinness Time Trees Triceps Brachii Muscle Vascular blood supply Vascular resistance afferent nerve arm experimental study femoral artery heart rhythm high risk knock-down mechanical stimulus mutant neuromechanism normotensive pharmacologic pressure prevent receptor response sensor vasoconstriction

项目摘要

PROJECT SUMMARY/ABSTRACT A reflex arising from contracting hind limb skeletal muscles is an important neural mechanism that is responsible for causing the cardiovascular adjustments to exercise. These adjustments, which include increases in peripheral vascular resistance, cardiac contractility and rate, function to increase arterial blood flow and oxygen to the exercising muscles, and in turn support their ability to contract. This neural mechanism has been named the exercise pressor reflex and its afferent arm is comprised of group III and IV fibers whose endings are located in and near the muscle interstitium. In patients with peripheral artery disease (PAD) the exercise pressor reflex is exaggerated. The overall goal of the experiments proposed in this application is to shed light on the role played by lactic acid in evoking the exercise pressor reflex in both health and simulated peripheral artery disease. The proposed experiments will pay particular attention to Acid Sensing Ion Channels (ASIC) and will focus on the role that they play in evoking the exaggerated exercise pressor reflex in PAD. Lactic acid, produced by contracting skeletal muscles is believed to stimulate group III and IV afferents, signaling the spinal cord and brainstem that the arterial blood supply to working muscle is not meeting its metabolic demand. In the proposed experiments, we will pay particular attention to two important ASIC isoforms, namely ASIC1a and ASIC3. We will examine in decerebrated unanesthetized rats the responses to contraction of group III and IV muscle afferents both before and after either pharmacological blockade of the above receptors or after they have been “knocked down” with siRNA. The proposed experiments will also examine the responses to contraction of these afferents before and after knockdown of myophosphorylase in the triceps surae muscles. In addition the responses of group III and IV afferents to contraction in mutant rats whose ASIC3 has been functionally inactivated by CRISPR Cas 9 technology will be determined. The proposed experiments will be performed both in rats with freely perfused femoral arteries and in rats with femoral arteries that have been ligated for 72 hours before the start of the experiment. The latter preparation simulates the arterial blood flow patterns seen in patients with PAD and therefore serves as a useful animal model of this disease. The proposed experiments are anticipated to provide new information about metabolic factors that cause the exercise pressor reflex to be exaggerated in PAD.

项目总结/摘要由收缩后肢骨骼肌引起的反射是重要的神经机制，负责引起心血管对运动的调节。这些调整包括外周血管阻力、心肌收缩力和心率增加，动脉血流量增加流动和氧气运动的肌肉，并反过来支持他们的收缩能力。这种神经机制被命名为运动加压反射，其传入臂由III和IV组纤维组成，末梢位于肌筋膜内和附近。在外周动脉疾病（PAD）患者中，运动加压反射被夸大。本申请中提出的实验的总体目标是阐明了乳酸在健康和模拟条件下诱发运动加压反射中的作用外周动脉疾病拟议的实验将特别关注酸敏感离子通道（ASIC），并将重点放在他们的作用，唤起夸张的运动升压反射在PAD。由骨骼肌收缩产生的乳酸被认为能刺激第三组和第四组传入神经，向脊髓和脑干发出信号，表明工作肌肉的动脉血液供应没有满足其代谢需求。在拟议的实验中，我们将特别注意两个重要的ASIC 同种型，即ASIC 1a和ASIC 3。我们将在去大脑的未麻醉大鼠中检查对收缩组III和IV肌肉传入之前和之后，无论是药理学封锁的或在它们被siRNA“敲低”之后。拟议的实验还将检查这些传入神经在肌磷酸化酶敲低前后对收缩的反应，小腿三头肌此外，突变大鼠的III和IV类传入对收缩的反应其ASIC 3已被CRISPR Cas 9技术功能性失活。的所提出的实验将在具有自由灌注股动脉的大鼠和具有自由灌注股动脉的大鼠中进行。在实验开始前已经结扎72小时的股动脉。后一种制剂模拟PAD患者的动脉血流模式，因此可作为有用的动物这种疾病的模式。预计拟议的实验将提供有关代谢的新信息。导致PAD患者运动加压反射增强的因素。