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

基本信息

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
项目类别：
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

项目摘要

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-II-IV感觉神经元上的分子受体检测到由于慢性心力衰竭，慢性阻塞性肺疾病（COPD）和其他慢性疲劳疾病而导致的肌肉代谢产物疲劳，这是严重的，衰弱的，使这些患者长期胜过预后不良。越来越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，有时会因治疗或出于未知原因而造成慢性。大量证据表明，III/IV组肌肉传入的周围感觉失调，自主神经功能障碍可能导致或导致过度慢性心力衰竭疲劳。我们的长期目标是确定向感觉和运动系统表明疲劳的基本机制，并确定导致心力衰竭和COPD等疾病疲劳增强的机制。在接下来的三年中，我们提出了对III/IV组肌肉传入神经元的分子受体的全面评估，这些神经元将这些专业的结尾赋予检测并发出肌肉收缩和运动随着肌肉代谢物的增加的能力。此处提出的实验将使用：1）创新的神经元收集和定量实时，PCR（QPCR），以确定哪些分子受体在III/IV组/IV传入神经元中有选择地表达。 2）钙成像，细胞收集和QPCR，以确定疲劳选择性神经元如何选择性地编码非代谢物的水平。 3）免疫组织化学确定表达的mRNA是否被翻译成插入膜中。 4）代谢物活化电流的全细胞记录以确定分子受体蛋白的功能； 5）在神经肌肉制备中进行单位电生理记录，以确定哪种代谢物在原位激活这些感觉神经元。这些实验的结果将为疲劳的概念提供基础科学背景，作为一个对心血管/自主系统，疲劳的感官感知体验和运动系统抑制具有强大影响的综合系统。这个概念以及发现的分子受体将导致对心力衰竭患者，COPD患者以及其他患有长时间，无法解释的疲劳的患者经历的过度疲劳的有效治疗。公共卫生相关性：慢性心力衰竭和慢性阻塞性肺部疾病通常与使这些患者患有心脏和呼吸道不足的疲劳相关。该提案将全面确定允许III/IV组传入神经元的分子受体检测产生的肌肉收缩，以及1）1）信号疲劳信号疲劳，导致“锻炼后施加反应”，通常会降低疲劳，2）降低机动系统的信号，以降低锻炼肌肉的能力，并在肌肉上进行锻炼区域，并在效率下进行效率，3）越来越强烈的感觉，并构成效率的效果，并构成效率的效率，并在3）效率上识别效果，并降低了锻炼的效果，并降低了锻炼的能力。了解这些受体将导致新的目标，以控制和治疗心血管疾病中过度，使人衰弱的疲劳。