Novel treatments of chronic pain due to repetitive mild traumatic brain injury

重复性轻度创伤性脑损伤引起的慢性疼痛的新疗法

• 批准号: 10754128
• 负责人: FLETCHER A WHITE
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754128
• 关键词: Affect; Animals; Anxiety; Area; Astrocytes; Basic Science; Behavioral; Binding; Biosensor; Brain; Brain Concussion; CASP1 gene; Caspase; Categories; Cells; Central Nervous System; Chronic; Clinical Sciences; Complex; Craniocerebral Trauma; Cytoplasm; Detection; Development; Diffuse Axonal Injury; Elderly; Enzyme-Linked Immunosorbent Assay; Event; Female; Functional disorder; Generations; Head; Human; IL18 gene; Immune System Diseases; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Kinetics; Luciferases; Maintenance; Mediating; Mediator; Memory impairment; Mental Depression; Microglia; Migraine; Minor; Modeling; Molecular; Monitor; Multiprotein Complexes; Mus; Nervous System; Neurobiology; Neurons; Nociception; Nucleotides; Oligodendroglia; Pain; Patient-Focused Outcomes; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Play; Population; Preparation; Process; Production; Protein Region; Proteins; Rehabilitation therapy; Reporter; Research; Role; Signal Transduction; Site; Specific qualifier value; Specificity; Stimulus; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Trauma; Veterans; Western Blotting; axon injury; blood-brain barrier crossing; brain cell; chronic pain; chronic pain management; chronic widespread pain; controlled cortical impact; cytokine; experimental study; falls; glial activation; immune cell infiltrate; improved; in vivo; in vivo imaging; inhibitor; injured; male; mild traumatic brain injury; neuroinflammation; neuron loss; neuropathology; novel; pain behavior; painful neuropathy; pharmacologic; pre-clinical; prevent; receptor; spatiotemporal; therapeutic target; therapeutically effective; white matter

PROJECT ABSTRACT A frequent condition observed in Veterans and civilian populations is a mild concussive event of the head due to a fall. Frequent falls and associated mild head injuries are a major problem among the older Veterans, especially males and can often lead to impaired memory, depression, anxiety and chronic pain. Numerous studies suggest that the chronic pain state is accompanied by neuroinflammation, though the regional and longitudinal profiles of this trauma-induced process contribution to long-term chronic pain neurobiology are largely unknown. Dysregulation of neuroinflammation following head injury may be modulated by Nod-like receptor protein 3 (NLRP3) inflammasome activation of caspase-1, the cysteine protease that cleaves numerous downstream targets, including pro-IL-1β and pro-IL-18 into their biologically active form. Sustained increase of these cytokines in the central nervous system, in turn, promotes chronic widespread pain that can affects multiple body sites. To better understand the processes which contribute to chronic pain due to a mild concussive event, we will use a transgenic mouse constitutively expressing a luciferase reporter of caspase-1 activation. Utilization of this transgenic mouse in combination with a murine closed-head concussive event is compatible with in vivo imaging and will allow us in the first aim to monitor the spatiotemporal dynamics of a neuroinflammation signaling cascade in the brain of younger and older male and female mice across time. These observations will likely correlate with the onset of chronic pain states. In the second aim, we will determine whether pharmacological inhibition of NLRP3 inflammasome assembly ameliorates chronic neuroinflammation and behavioral correlates of pain in mice. Together, these Aims will provide crucial information on the function of a regulator of neuroinflammation in vivo across time and the degree to which NLRP3 targeting may be a viable therapeutic strategy in head injury- induced chronic pain states.

项目摘要 在退伍军人和平民中观察到的常见情况是由于以下原因导致的头部轻度震荡事件 一次跌倒。频繁跌倒和相关的轻度头部受伤是老年退伍军人的一个主要问题，尤其是 男性，通常会导致记忆力受损、抑郁、焦虑和慢性疼痛。大量研究表明 慢性疼痛状态伴随着神经炎症，尽管区域和纵向分布 这种创伤引起的过程对长期慢性疼痛神经生物学的贡献在很大程度上尚不清楚。 Nod 样受体蛋白 3 可能调节头部损伤后神经炎症的失调 (NLRP3) 炎症小体激活 caspase-1，半胱氨酸蛋白酶可裂解大量下游 靶标，包括将 pro-IL-1β 和 pro-IL-18 转化为其生物活性形式。这些细胞因子持续增加 在中枢神经系统中，反过来会促进慢性广泛疼痛，影响身体多个部位。到 为了更好地了解轻度震荡事件导致慢性疼痛的过程，我们将使用 组成型表达 caspase-1 激活的荧光素酶报告基因的转基因小鼠。利用这个 转基因小鼠与小鼠闭头脑震荡事件相结合，与体内成像兼容 并使我们能够实现监测神经炎症信号级联的时空动态 随着时间的推移，在年轻和年老的雄性和雌性小鼠的大脑中。这些观察结果可能与 慢性疼痛状态的发作。在第二个目标中，我们将确定是否有药物抑制 NLRP3炎症小体组装可改善慢性神经炎症和疼痛的行为相关性 老鼠。总之，这些目标将提供有关神经炎症调节剂功能的重要信息。 体内随时间的变化以及 NLRP3 靶向可能成为头部损伤的可行治疗策略的程度- 诱发慢性疼痛状态。