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 收缩后肢骨骼肌产生的反射是重要的神经机制 负责导致心血管调整进行运动。这些调整包括 外周血管抗性，心脏收缩性和速率增加，增加动脉血液的功能 流向运动肌肉的氧气，进而支持其收缩能力。这种神经机制 已被命名为练习式压力反射，其传入臂已完成III组和IV纤维的完成 末端位于肌肉间质中和附近。在周围动脉疾病（PAD）的患者中 锻炼压力反射被夸大了。本应用程序提出的实验的总体目标是 阐明了乳酸在健康和模拟中唤起运动压力反射中的作用 周围动脉疾病。提出的实验将特别注意酸性离子通道 （ASIC），并将专注于他们在唤起垫子中夸大的锻炼后反射中所扮演的角色。 据信，通过收缩骨骼肌产生的乳酸会刺激III和IV组的传入， 向脊髓和脑干发出信号，表明动脉血液供应为工作肌肉不满足 代谢需求。在拟议的实验中，我们将特别注意两个重要的ASIC 同工型，即ASIC1A和ASIC3。我们将在未屈服的大鼠中检查对 在任何药理学阻滞之前和之后，III组和IV肌传入的收缩 在受体上方或被siRNA“撞倒”之后。提出的实验也将 检查在敲除肌磷酸化合物之前和之后对这些传入的收缩的反应 三头肌肌肉。此外 将确定其ASIC3在功能上已被CRISPR CAS 9技术灭活。这 提出的实验将在自由灌注股动脉的大鼠中进行 在实验开始之前已经连接了72小时的股动脉。后来的准备 模拟PAD患者中看到的动脉血流模式，因此可以用作有用的动物 这种疾病的模型。预计拟议的实验将提供有关代谢的新信息 导致运动式训练反射的因素被夸大。