ASICs as metabolic sensors in muscle afferents

ASIC 作为肌肉传入的代谢传感器

• 批准号: 8138086
• 负责人: CHRISTOPHER J BENSON
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138086
• 关键词: ASIC channel; Address; Afferent Neurons; Cardiovascular Diseases; Chemicals; Chronic; Complex; Data; Development; Disease; Disease Progression; Electrophysiology (science); Exercise; Exercise Tolerance; Fibromyalgia; Future; Genes; Genetic; Goals; Health; Heart failure; Hospitalization; Hypertension; In Vitro; Injury; Investigation; Ischemia; Kidney Failure; Label; Mediating; Mediator of activation protein; Metabolic; Molecular; Molecular Target; Mus; Muscle; Muscle Cells; Muscle Fatigue; Mutagenesis; Myalgia; Myocardium; Nerve; Output; Pain; Patch-Clamp Techniques; Patients; Performance; Peripheral Vascular Diseases; Pharmacological Treatment; Play; Preparation; Property; Proteins; Publishing; Reflex action; Regulation; Role; Sickle Cell Anemia; Signal Transduction; Skeletal Muscle; Stress; Sympathetic Nervous System; Testing; United States; Variant; Vascular blood supply; Veterans; abstracting; afferent nerve; claudication; desensitization; extracellular; in vivo Model; inorganic phosphate; insight; meetings; novel; public health relevance; receptor; relating to nervous system; sensor; tool

DESCRIPTION (provided by applicant): Project Summary/Abstract During maximal exercise or ischemia, blood supply is insufficient to meet the metabolic needs of skeletal muscle, and so metabolic by-products are produced and accumulate. Sensory nerves (afferents) that innervate muscle respond to these changes in the metabolic milieu, and send signals centrally. These signals can initiate exercise-mediated reflexes, and sometimes they signal muscle pain. Multiple chemicals have been shown to activate muscle afferents, but the molecular identity of the receptors that sense these chemicals are not well understood. Acid-Sensing Ion Channels (ASICs) are suited to sense extracellular chemical changes in muscle. Our overall goal is to understand the role of ASICs as receptors in muscle afferents during the related conditions of muscle ischemia and exercise. A strength of our proposal is that we have developed tools to unravel the components of muscle afferent activation at the molecular level. These studies will advance our understanding of how muscle afferents sense pain and exercise, and provide a target for future studies and potential therapies. Specifically, our Aims are to: 1) determine the subunit composition of ASIC channels in skeletal muscle afferents; 2) define the mechanisms by which ASICs are modulated by other metabolites; and 3) determine the role of ASICs metaboreceptors during ischemia and exercise. These studies will provide significant insight into the molecular mechanisms that underlie painful conditions such as claudication from peripheral vascular disease, pain associated with sickle cell disease, fibromyalgia, muscle injury, and other painful muscle conditions. Additionally, our results will provide molecular insight into the mechanisms how muscle afferents sense metabolic changes in muscle and activate exercise-mediated reflexes. Moreover, our studies have implications for common cardiovascular diseases. Heart failure is now the most common cause for hospitalization in the United States. It is well understood, that increases in the sympathetic nervous system plays a major role in the progression of the disease, and much of our pharmacological treatments are aimed at blocking this sympathoexcitation. Muscle afferent activity is one of the major mechanisms contributing to this high sympathetic tone, and alterations of muscle reflexes are believed to contribute to the poor exercise tolerance of patients with heart failure. Increasing evidence points to ASICs as a major sensor of the metabolic milieu of muscle, and better understanding of their role could provide a molecular target to treat muscle pain and cardiovascular diseases.

描述（由申请人提供）： 项目概要/摘要在最大运动量或缺血时，血液供应不足以满足骨骼肌的代谢需要，从而产生并积累代谢副产物。支配肌肉的感觉神经（传入神经）对代谢环境的这些变化做出反应，并集中发送信号。这些信号可以启动运动介导的反射，有时它们会发出肌肉疼痛的信号。多种化学物质已被证明可以激活肌肉传入，但感知这些化学物质的受体的分子特性尚不清楚。酸感应离子通道 (ASIC) 适用于感应肌肉中的细胞外化学变化。我们的总体目标是了解 ASIC 在肌肉缺血和运动相关条件下作为肌肉传入受体的作用。我们建议的一个优势是我们开发了工具来在分子水平上揭示肌肉传入激活的组成部分。这些研究将增进我们对肌肉传入如何感知疼痛和运动的理解，并为未来的研究和潜在的治疗提供目标。具体来说，我们的目标是：1）确定骨骼肌传入中 ASIC 通道的亚基组成； 2) 定义 ASIC 被其他代谢物调节的机制； 3) 确定 ASIC 代谢感受器在缺血和运动期间的作用。这些研究将深入了解疼痛病症的分子机制，例如周围血管疾病导致的跛行、镰状细胞病相关的疼痛、纤维肌痛、肌肉损伤和其他肌肉疼痛病症。此外，我们的结果将为肌肉传入如何感知肌肉代谢变化并激活运动介导的反射的机制提供分子见解。此外，我们的研究对常见的心血管疾病也有影响。心力衰竭现在是美国住院最常见的原因。众所周知，交感神经系统的增强在疾病的进展中起着重要作用，我们的许多药物治疗旨在阻断这种交感神经兴奋。肌肉传入活动是导致这种高交感神经紧张的主要机制之一，并且肌肉反射的改变被认为是导致心力衰竭患者运动耐量差的原因之一。越来越多的证据表明 ASIC 是肌肉代谢环境的主要传感器，更好地了解它们的作用可以为治疗肌肉疼痛和心血管疾病提供分子靶点。