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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.

项目概要/摘要后肢骨骼肌收缩产生的反射是一种重要的神经机制负责引起心血管对运动的调整。这些调整包括增加外周血管阻力、心肌收缩力和速率、增加动脉血的功能为运动肌肉提供流量和氧气，进而支持其收缩能力。这种神经机制被称为运动加压反射，其传入臂由第 III 组和第 IV 组纤维组成，其末端位于肌肉间质内及其附近。在患有外周动脉疾病 (PAD) 的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揭示了乳酸在激发健康和模拟运动升压反射中所起的作用周围动脉疾病。拟议的实验将特别关注酸传感离子通道 (ASIC) 并将重点关注它们在诱发 PAD 中过度运动升压反射方面所发挥的作用。骨骼肌收缩产生的乳酸被认为可以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未满足其要求代谢需求。在所提出的实验中，我们将特别关注两个重要的 ASIC 同工型，即 ASIC1a 和 ASIC3。我们将在未麻醉的去脑大鼠中检查对在药物阻断之前和之后，第 III 组和第 IV 组肌肉传入的收缩上述受体或它们被 siRNA“击倒”后。拟议的实验还将检查肌磷酸化酶敲低前后这些传入神经收缩的反应小腿三头肌。此外，第三组和第四组传入神经对突变大鼠收缩的反应将确定其ASIC3已被CRISPR Cas 9技术功能失活。这拟议的实验将在股动脉自由灌注的大鼠和股动脉自由灌注的大鼠中进行实验开始前已结扎72小时的股动脉。后期准备模拟 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型。拟议的实验预计将提供有关代谢的新信息导致 PAD 运动升压反射过度的因素。