Mechanisms of muscle afferent sensitization after ischemia

缺血后肌肉传入敏化机制

• 批准号: 10471379
• 负责人: Michael P Jankowski
• 金额: $ 49.68万
• 依托单位: CINCINNATI CHILDRENS HOSP 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: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471379
• 关键词: Ablation; Acute; Affect; Afferent Neurons; Automobile Driving; Behavior; Behavioral; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell Nucleus; Cells; Chronic; Complement; Data; Development; Disease; Electrophysiology (science); Elements; Exercise; Family; Family member; Female; Formulation; Gene Expression; Genes; Goals; Growth Factor; Health; Hematological Disease; Immune; Individual; Injury; Interleukin-1; Interleukin-1 Receptors; Ischemia; Knock-out; Knowledge; Lead; Mediating; Molecular; Mus; Muscle; Muscle Fibers; Musculoskeletal Pain; Myalgia; Nerve; Neurobiology; Nociceptors; Outcome; Pain; Pain Measurement; Pain Threshold; Pathway interactions; Perfusion; Peripheral; Peripheral Nerves; Peripheral Vascular Diseases; Persistent pain; Persons; Play; Population; Preparation; Prevalence; Process; Property; RNA Sequences; RNA-Binding Proteins; Reflex action; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Role; Sex Differences; Sickle Cell Anemia; Signal Transduction; Skeletal Muscle; Skin; Small Interfering RNA; Source; Spinal Cord; Spinal Ganglia; Testing; Tissues; Transgenic Organisms; United States; Up-Regulation; base; behavioral response; cytokine; experience; experimental study; glial cell-line derived neurotrophic factor; in vivo; innovation; insight; knock-down; macrophage; male; member; mouse model; neurotrophic factor; novel; novel therapeutics; prevent; ras Oncogene; receptor; response; sensory mechanism; sex; transcription factor

Abstract: While great deal is understood about mechanisms of sensory transduction from the skin, relatively little is known about this process from the muscles. As peripheral injuries resulting from repetitive ischemic/reperfusion (I/R) are a major health issue that affects millions of people in the United States, this gap in knowledge precludes us from identifying specific therapies for muscle pain or altered cardiovascular responses to exercise in the context of ischemia. Peripheral I/R occurs in blood disorders such as sickle cell disease, and in cardiovascular disorders such as peripheral vascular disease. Males and females display different features of myalgia and exercise pressor reflexes (EPRs) under conditions of reduced peripheral perfusion. The major goal of this study is to determine the sex specific molecular mechanisms of muscle afferent sensitization that may underlie the transition from acute to chronic ischemic myalgia. Pilot data in murine models of repetitive I/R injury suggest that peripheral sensitization in males is regulated by increased DRG gene expression that is modulated by glial cell line-derived neurotrophic factor (GDNF) family receptor 1 (GFR1) in muscle nociceptors. In females, afferent sensitization, pain-related behaviors and altered EPRs after repeated I/R injury may be regulated by increased interleukin 1 receptor type 1 (IL1r1) dependent gene expression. We hypothesize that the prolonged effects of successive I/R injuries are mediated by GDNF related peripheral sensitization in males and IL1 induced sensitization in females. Aim 1 will determine if myofiber produced GDNF and DRG upregulation of GFR1, regulate the observed changes in muscle afferent response properties, pain-related behaviors and altered EPRs after dual I/R in males. We will use muscle fiber specific GDNF ablation or our novel in vivo siRNA-mediated knockdown of genes in single peripheral nerves in conjunction with our ex vivo muscle afferent recording preparations or assays of pain-like behaviors and EPRs. Aim 2 will utilize a similar approach except we will determine if macrophage produced IL1 or DRG upregulation of IL1r1, regulate the novel changes in female muscle afferents or behaviors after successive I/R. Finally, Aim 3 will use ex vivo recording and pain-related behavioral analyses to determine if expression differences in AU-rich element RNA-binding protein 1 (AUF1) or the ras family member, RAN, modulates the sex specific effects of successive I/R injuries between females versus males. Each of these aims will be complemented by analysis of DRG and muscle gene expression. The studies outlined here will also provide a novel direction in muscle neurobiology research that will go well beyond the incremental expansion of current reports. Results will enable us to identify unique sex dependent mechanisms associated with muscle afferent sensitization that underlie acute to chronic ischemic myalgia development after I/R injury. This may lead to the formulation of more appropriate treatments for musculoskeletal pain or altered EPRs associated with ischemia/ reperfusion that target the proper receptor(s), primary afferent subpopulation(s) or peripheral target tissues.

摘要：虽然对皮肤的感觉翻译机制有很多了解，但相对相对 从肌肉中对这个过程知之甚少。随着重复的外围伤害导致 缺血/再灌注（I/R）是一个主要的健康问题，影响了美国数百万的人，这一差距 从识别肌肉疼痛或心血管改变的特定疗法之前就知道了 在缺血的背景下对运动的反应。外围I/R发生在血液疾病（例如镰状细胞）中 疾病以及心血管疾病（如周围血管疾病）。男性和女性展示 肌痛和运动压力反射（EPRS）的不同特征在降低外周的条件下 灌注。这项研究的主要目标是确定肌肉的性别特定分子机制 传入的敏化可能是从急性到慢性缺血性肌痛的过渡。飞行员数据中 重复I/R损伤的鼠模型表明，男性的周围敏感性受到增加 受神经胶质细胞系衍生的神经营养因子（GDNF）家族接收器调节的DRG基因表达 （gfr1）在肌肉伤害感受器中。在女性中，传入敏化，与疼痛相关的行为和EPR改变 重复后的I/R损伤后，可能会受到白介素1接收器1型（IL1R1）依赖基因的调节 表达。我们假设成功I/R损伤的长期影响是由GDNF介导的 男性和IL1诱导女性敏感性的相关外周灵敏度。 AIM 1将确定是否 肌纤维产生GFR1的GDNF和DRG上调，调节观察到的肌肉传入的变化 男性双I/R后，反应特性，与疼痛相关的行为和EPR改变。我们将使用肌肉纤维 特定的GDNF消融或我们的小说在体内siRNA介导的单个外周神经中基因的敲低 与我们的离体肌肉传入记录制剂或类似疼痛行为和EPR的测定的结合。 AIM 2将使用类似的方法，除非我们确定巨噬细胞是产生IL1还是DRG IL1R1的上调，调节成功I/R后女性肌肉传入或行为的新颖变化。 最后，AIM 3将使用离体记录和与疼痛相关的行为分析来确定是否表达 富含AU的元素RNA结合蛋白1（AUF1）或RAS家族成员的差异，RAN，调节 女性与男性之间成功I/R损伤的性别特异性影响。这些目标将是 通过分析DRG和肌肉基因表达完成。这里概述的研究还将提供 肌肉神经生物学研究的新方向将远远超出电流的增量扩张 报告。结果将使我们能够确定与肌肉传入相关的独特性依赖性机制 I/R损伤后，急性对慢性缺血性肌痛发育的敏感性。这可能会导致 形成更合适的治疗肌肉骨骼疼痛或与缺血/相关的EPR的治疗方法 靶向适当的接收器，主要传入亚群或外围目标时间的再灌注。