Molecular receptors on Group III-IV sensory neurons detecting muscle metabolites

III-IV组感觉神经元上的分子受体检测肌肉代谢物

• 批准号: 8239123
• 负责人: ALAN R LIGHT
• 金额: $ 48.17万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239123
• 关键词: Address; Affect; Afferent Neurons; Area; Basic Science; Behavior; Blood Pressure; Blood Vessels; Blood flow; Brain; Calcium; Cardiac; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Chronic; Chronic Fatigue Syndrome; Chronic Obstructive Airway Disease; Clinical; Cognitive; Contracts; Detection; Disease; Doctor of Philosophy; Esthesia; Evaluation; Exercise; Fatigue; Flaccid Muscle Tone; Future; Goals; Harvest; Heart Rate; Heart failure; Image; Immunohistochemistry; In Situ; Injury; Investigation; Iowa; Knowledge; Label; Laboratories; Lead; Light; Location; Lung diseases; Membrane; Memory; Messenger RNA; Methods; Molecular; Motor; Mus; Muscle; Muscle Contraction; Myalgia; Nerve Endings; Nerve-Muscle Preparations; Neurons; Nociception; North Carolina; Outcome; P2X-receptor; Painless; Patients; Perception; Peripheral; Physiological; Play; Preparation; Proteins; Protons; Quality of life; Reflex action; Regulatory Pathway; Research; Respiratory Insufficiency; Respiratory Muscles; Rest; Role; Sensory; Signal Transduction; Skeletal Muscle; Spinal; Stroke Volume; Sympathetic Nervous System; System; TRPV1 gene; Time; Translating; Universities; Vasodilation; Whole-Cell Recordings; Work; cancer therapy; cellular imaging; drug development; effective therapy; exhaustion; experience; gene discovery; innovation; neuronal cell body; novel; outcome forecast; prevent; receptor; research study; response; selective expression; sensorimotor system; sensory mechanism; sensory system; treatment effect; vasoconstriction

DESCRIPTION (provided by applicant): Molecular receptors on Group III-IV sensory neurons detecting muscle metabolites Fatigue due to chronic heart failure, chronic obstructive pulmonary disorder (COPD), and other chronic fatiguing disorders is serious, debilitating, and creates poor prognoses for long-term outcomes in these patients. Many more patients are affected by idiopathic, injury, or disease-caused short-term fatigue and myalgia that sometimes remits with treatment or for unknown reasons becomes chronic. Considerable evidence indicates that peripheral sensory dysregulation of group III/IV muscle afferents, and autonomic dysregulation may cause or contribute to the excessive fatigue of chronic heart failure. Our long-term goal is to determine the fundamental mechanisms that signal fatigue to sensory and motor systems, and determine the mechanisms that cause enhanced fatigue in diseases such as heart failure and COPD. In the next three years, we propose a comprehensive evaluation of the molecular receptors on group III/IV muscle afferent neurons that endow these specialized endings with the ability to detect and signal the increases in muscle metabolites that occur with muscle contraction and exercise. Experiments proposed here will use: 1) innovative neuron harvesting and quantitative real-time, PCR (qPCR) to determine which molecular receptors are expressed selectively in group III/IV afferent neurons. 2) calcium imaging, cell harvesting and qPCR to determine how fatigue-selective neurons selectively encode non-painful levels of metabolites. 3) immunohistochemistry to determine if mRNA expressed is translated protein inserted into membrane. 4) whole-cell recording of metabolite activated currents to determine the function of the molecular receptor proteins; and 5) single unit electrophysiological recording in a nerve muscle preparation to determine which metabolites activate these sensory neurons in situ. The results of these experiments will provide the basic science background for the concept of fatigue as an integrated system with powerful influence on the cardiovascular/autonomic system, the sensory-perceptual experience of fatigue, and motor system inhibition. This concept, and the molecular receptors discovered will lead to rational, targeted effective treatments for the excessive fatigue experienced by heart failure patients, patients with COPD, and other patients suffering from prolonged, unexplained fatigue. PUBLIC HEALTH RELEVANCE: Chronic heart failure and chronic obstructive pulmonary disease are commonly associated with debilitating fatigue that is not consistent with the cardiac and respiratory insufficiencies these patients have. This proposal will comprehensively determine the molecular receptors that allow group III/IV afferent neurons to detect muscle contraction produced metabolites, and 1) signal fatigue the sympathetic nervous system causing the "exercise pressor response" that normally reduces fatigue, 2) signal the motor system to reduce the ability to contract exercising muscle, and 3) signal the sensory areas of the brain leading to the overwhelming sensation of fatigue. Knowing these receptors will lead to new targets to control and treat excessive, debilitating fatigue in cardiovascular disorders.

描述（由申请人提供）：III-IV组感觉神经元上的分子受体检测肌肉代谢物慢性心力衰竭，慢性阻塞性肺疾病（COPD）和其他慢性疲劳疾病引起的疲劳是严重的，使人衰弱，并对这些患者的长期预后造成不良影响。更多的患者受到特发性、损伤或疾病引起的短期疲劳和肌痛的影响，这些疲劳和肌痛有时会随着治疗而缓解，或由于未知的原因而变成慢性的。大量证据表明，III/IV组肌肉传入神经的外周感觉失调和自主神经失调可能导致或促进慢性心力衰竭的过度疲劳。我们的长期目标是确定向感觉和运动系统发出疲劳信号的基本机制，并确定导致心力衰竭和慢性阻塞性肺病等疾病中疲劳增强的机制。在接下来的三年里，我们将对III/IV组肌肉传入神经元上的分子受体进行全面评估，这些分子受体赋予这些特殊末梢检测肌肉收缩和运动时肌肉代谢物增加的能力。这里提出的实验将使用：1)创新的神经元采集和定量实时PCR （qPCR）来确定哪些分子受体在III/IV组传入神经元中选择性表达。2)钙成像，细胞收集和qPCR来确定疲劳选择性神经元如何选择性地编码非疼痛代谢产物水平。3)免疫组化检测mRNA表达是否为插入膜的翻译蛋白。4)全细胞记录代谢物激活电流，以确定分子受体蛋白的功能；5)在神经肌肉准备中进行单单元电生理记录，以确定哪些代谢物在原位激活这些感觉神经元。这些实验结果将为疲劳作为一个对心血管/自主神经系统、疲劳的感觉-知觉体验和运动系统抑制有强大影响的综合系统的概念提供基础科学背景。这一概念以及发现的分子受体将为心力衰竭患者、慢性阻塞性肺病患者和其他长期无法解释的疲劳患者带来合理、有针对性的有效治疗。