GCAMP6 mice for determination of mechanisms of chronic muscle ache, pain and fatigue

GCAMP6 小鼠用于确定慢性肌肉疼痛、疼痛和疲劳的机制

• 批准号: 9260952
• 负责人: ALAN R LIGHT
• 金额: $ 18.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260952
• 关键词: Ache; Afferent Neurons; Blood Vessels; Blood capillaries; Calcium; Cardiovascular system; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Chronic Headaches; Cognitive; Comorbidity; Data; Digit structure; Duct (organ) structure; Electrophysiology (science); Esthesia; Fascia; Fatigue; Fiber; Fibromyalgia; Gastrocnemius Muscle; Goals; Headache Disorders; Image; In Vitro; Investigation; Location; Lymphatic; Lymphatic Diseases; Lymphatic vessel; Mechanics; Mechanoreceptors; Methods; Migraine; Molecular; Mus; Muscle; Muscle Fatigue; Myalgia; Myofacial Pain; Nature; Nerve; Nerve Fibers; Neurons; Nociceptors; Pain; Patients; Photons; Physiological; Play; Preparation; Property; Protons; Quality of life; Reflex action; Reporter; Research Personnel; Role; Sensory; Signal Pathway; Signal Transduction; Skeletal Muscle; Spinal Ganglia; Structure; Symptoms; Temporomandibular Joint Disorders; Tendon structure; Tension Headache; Time; Transgenic Mice; afferent nerve; capillary; chronic pain; human subject; in vivo; mouse model; muscular structure; nerve supply; neurotransmission; promoter; public health relevance; receptor; response; sensor; sensorimotor system; sensory mechanism; tool; translational study; trigger point

 DESCRIPTION (provided by applicant): GCAMP6 mice for determination of mechanisms of chronic muscle ache, pain and fatigue. Muscle pain and muscle fatigue are symptoms in many chronic diseases including Fibromyalgia, Chronic Fatigue Syndrome, Myofacial Pain, Chronic Tension Headache, and Temporomandibular Disorder. Many more patients have degraded quality of life because of short term myalgia and fatigue that sometimes remits with treatment, or for unknown reasons, becomes chronic. Our long term goal is to determine the fundamental mechanisms that signal intense muscle pain, ache and fatigue to sensory and motor systems. We have previously used discoveries in mouse models to prove that combinations of protons, lactate, and ATP are necessary and sufficient to activate muscle sensory neurons. In translational studies in human subjects we showed that combination of these three metabolites activated the sensations of muscle ache and fatigue in human subjects. Here we propose to create a transgenic mouse that will make it possible, for the first time, to image the activity of sensory neurons that signal pain and fatigue in functioning skeletal muscle. This will allow us to establish the molecular and cellular mechanisms of the sensory signaling pathways for cognitive sensations of muscle pain and muscle fatigue. It will also make it possible to directly observe the mechanisms of several controversial phenomena in muscle pain including trigger points, the pulsating nature of muscle ache and chronic and migraine headache, lymphatic disease association with muscle fatigue and muscle pain, and sympathetic activation enhancement of muscle pain. The specific aims for this proposal are: 1) Create mice that have endogenous calcium sensors with promoters that allow expression in Group III/IV muscle innervating sensory neurons. 2) Use these mice to record III/IV afferents responses to low and high metabolites using anesthetized in vivo preparations. This will allow comparisons with the digit muscle recordings collected from teased muscle nerve fibers previously, and dorsal root ganglion neurons recorded with calcium imaging. With this method we will also determine the location and structures that physiologically identified Group III/IV receptor endings innervate (both nociceptors and ergoreceptors of all types e.g., mechanoreceptor and metaboreceptor).

 描述（由适用提供）：用于确定慢性肌肉疼痛，疼痛和疲劳机制的GCAMP6小鼠。肌肉疼痛和肌肉疲劳是许多慢性疾病的症状，包括纤维肌痛，慢性疲劳综合征，肌膜疼痛，慢性张力头痛和颞下颌疾病。由于短期的肌痛和疲劳，有时会因治疗或出于未知原因而变得慢性，因此更多的患者降解了生活质量。我们的长期目标是确定对感官和运动系统的强烈肌肉疼痛，疼痛和疲劳的基本机制。我们以前已经使用小鼠模型中的发现来证明质子，裂纹和ATP的组合是必要的，足以激活肌肉感觉神经元。在人类受试者的翻译研究中，我们表明，这三种代谢产物的组合激活了人类受试者的肌肉疼痛和疲劳的感觉。在这里，我们建议创建一种转基因小鼠，该小鼠将首次成为可能的感觉神经元的活性，该运动神经元在功能骨骼肌肉功能中信号疼痛和疲劳。这将使我们能够建立肌肉疼痛和肌肉疲劳的认知感觉的感觉信号通路的分子和细胞机制。它还可以直接观察机制2）使用具有内源性钙传感器的这些小鼠与启动子与允许在III/IV组中表达的启动子，这些小鼠神经感官神经元。记录III/IV传入对低代谢产物和高代谢产物的反应，使用麻醉的体内制剂。这将允许与以前从嘲笑的肌肉神经纤维中收集的数字肌肉记录进行比较，以及用钙成像记录的背根神经神经元。使用此方法，我们还将确定物理鉴定的III/IV受体末端的位置和结构（所有类型的伤害感受器和成真受体），例如机械感受器和分类受体受体）。