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

• 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
• 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

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.

项目摘要/摘要 后肢骨骼肌收缩产生的反射是一种重要的神经机制，即 负责使心血管调节进行锻炼。这些调整包括 外周血管阻力、心脏收缩能力和心率的增加，增加动脉血的功能 向运动肌肉输送氧气，进而支持肌肉的收缩能力。这种神经机制 已被命名为运动加压反射，其传入臂由III和IV类纤维组成，其 末梢位于肌肉间质及其附近。外周动脉疾病(PAD)患者 运动升压反射被夸大了。本应用程序中提出的实验的总体目标是 阐明乳酸在运动加压反射中所起的作用 外周动脉疾病。拟议的实验将特别关注酸敏离子通道 (ASIC)，并将专注于它们在唤起PAD中夸大的运动加压反射中所起的作用。 骨骼肌收缩产生的乳酸被认为刺激第三类和第四类传入， 向脊髓和脑干发出信号，表明供应给工作肌肉的动脉血不能满足其需求 代谢需求。在建议的实验中，我们将特别关注两个重要的ASIC 亚型，即ASIC1a和ASIC3。我们将在去大脑的未麻醉大鼠身上检测对 第III和IV组肌肉传入神经在药物阻断前后的收缩 在受体之上或在它们被siRNA“击倒”之后。拟议中的实验还将 检测肌磷酸酶基因敲除前后这些传入神经对收缩的反应 小腿三头肌。此外，基因突变大鼠的第III和IV类传入神经对收缩的反应 将确定谁的ASIC3已被CRISPR Cas 9技术功能失活。这个 拟议的实验将在股动脉自由灌流的大鼠和 在实验开始前，已经结扎了72小时的股动脉。后者的准备工作 模拟PAD患者的动脉血流模式，因此是一种有用的动物 这种疾病的典范。拟议的实验有望提供有关新陈代谢的新信息。 导致运动加压反射在PAD中被夸大的因素。