Heat therapy for the treatment of SCI-induced changes in nociceptor and mitochondrial function

热疗法治疗 SCI 引起的伤害感受器和线粒体功能变化

• 批准号: 10641385
• 负责人: OLIVIA ELLER
• 金额: --
• 依托单位: KANSAS CITY 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: 2023-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641385
• 关键词: Acute; Address; Antioxidants; Apoptosis; Area; Attenuated; Award; Biology; Calcium; Cells; Chest; Chronic; Chronic Phase; Cities; Clinical; Complication; Contusions; Data; Development; Disease; Edema; Educational process of instructing; Electrophysiology (science); Environment; Esthesia; Ethics; Fiber; Functional disorder; Funding; Goals; Health; Healthcare; Heat-Shock Proteins 70; Homeostasis; Hour; Human; Hydrogen Peroxide; Hyperactivity; Hypersensitivity; Individual; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Kansas; Knowledge; Learning; Lesion; Locomotor Recovery; Manuscripts; Measures; Medical; Medical center; Mentored Research Scientist Development Award; Mentors; Metabolic; Metabolic dysfunction; Mitochondria; Molecular; Mus; Nerve Fibers; Neurons; Neuropathy; Nociceptors; Nonpharmacologic Therapy; Opioid; Outcome; Oxidative Stress; Pain; Pain management; Patients; Peripheral; Peripheral Nervous System Diseases; Persistent pain; Phase; Placebos; Production; Proteins; Publishing; Qualifying; Reactive Oxygen Species; Recovery; Rehabilitation therapy; Research; Research Technics; Resistance; Resources; Running; Scientist; Secondary to; Services; Severities; Skin; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord injury; Stress; Structure; Surgical Injuries; Techniques; Temperature; Testing; Therapeutic Intervention; Therapeutic heat application; Time; Tissues; Training; Translating; Transmission Electron Microscopy; Trauma; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Vertebral column; Veterans; Work; Writing; care burden; career development; chronic pain; chronic pain management; cytokine; density; excitotoxicity; experience; graduate student; human subject; improved; improved outcome; mitochondrial dysfunction; neural; neuron loss; neuronal cell body; neurotransmission; non-opioid analgesic; opioid epidemic; opioid misuse; pain behavior; pain outcome; pharmacologic; prescription opioid; prevent; programs; respiratory; skills; spinal cord injury pain; spontaneous pain; symposium

An estimated 42,000 of the individuals living with spinal cord injury (SCI) are Veterans, which adds a significant health care burden to the Department of Veterans Affairs (VA) as SCI results in numerous long-term complications. One long-term complication is chronic pain, which is often rated among the most significant complaints of individuals with SCI. Opioids are prescribed to treat SCI-induced pain even though they have contributed to opioid misuse disorders and can actually worsen pain and delay recovery. Changes in nociceptor function, or the neurons that transmit pain, are thought to play a role in SCI-induced pain. Our lab has found that thoracic spinal contusion injury in mice results in the development of spontaneous pain behavior, nociceptor hypersensitivity, increased inflammation, and neuropathy in the skin. Our preliminary data also suggest that SCI causes mitochondrial dysfunction in the dorsal root ganglia (DRG), which is where neuronal cell bodies reside. Dysfunctional mitochondria are known to contribute to the secondary phase of SCI through production of reactive oxygen species (ROS), apoptosis, and aberrant calcium homeostasis, which can ultimately lead to neuronal cell death. Taken together, our data suggest that following SCI, neuronal mitochondria are not functioning properly, which could contribute to increased inflammation and neuropathy and subsequent development of nociceptor hypersensitivity and pain. Therefore, we are proposing the use of repeated heat treatment (rHT) following SCI in mice because this therapy has been shown to restore mitochondrial function, decrease mitochondrial ROS and inflammation, and improve pain outcomes. We will also determine if starting repeated rHT during either the acute or chronic phase of SCI, has different outcomes. Aim 1 of this proposal will determine the influence of rHT on SCI-induced pain, nociceptor dysfunction, and neuropathy while Aim 2 will determine the effect of rHT on mitochondrial function and content and ROS production following SCI. Aim 2 will also explore if targeting mitochondrial ROS with a mitochondrial specific antioxidant improves outcomes of SCI. We hypothesize that by restoring mitochondrial function and reducing widespread inflammation with rHT, nociceptor hypersensitivity, neuropathy, and pain will be attenuated. Dr. Eller’s background and training thus far make her a strong candidate for this award. She has mastered the SCI surgery and will now be trained by two experts, Dr. Kyle Baumbauer and Dr. John Thyfault, on techniques related to characterizing nociceptor and mitochondrial function, respectively. Her co-mentors are highly qualified scientists that have committed time and resources for Dr. Eller’s career development. In addition, the scientific environments at the University of Kansas Medical Center (KUMC) and the Kansas City VA Medical Center (VAMC) will allow Dr. Eller to not only complete the proposed research but also aid in her career development. She will expand her background knowledge in SCI and mitochondrial biology through relevant course work, seminars, and conferences. She will improve her presentation, writing, and mentoring skills by presenting her work at national conferences, publishing manuscripts, and teaching and mentoring graduate students. Finally, she will take the data generated from this proposal and apply for subsequent funding including a VA CDA-2 and NIH K01 award. Dr. Eller’s long-term goal is to establish herself as an independent VA Research Scientist and an expert in SCI pain. The CDA-1 would help her accomplish her goals by allowing her to learn new research techniques, expand her knowledge about SCI pain and mitochondria dysfunction, improve her writing and presentation skills, learn how to run a successful and ethical research program, and helping her integrate into the Kansas City VAMC. This award will also positively benefit the VA because the proposal addresses multiple areas of the VA RR&D service including a non-opioid and non-pharmacological therapy for chronic pain, a molecular study exploring the mechanisms of action of rehabilitative intervention by focusing on changes to the mitochondria, and the potential to translate to human subjects.

估计有42,000人患有脊髓损伤（SCI）的人是退伍军人，这增加了 大量的医疗保健伯恩伯恩（Burnen）向退伍军人事务部（VA）进行SCI，导致了许多长期 并发症。一种长期并发症是慢性疼痛，通常被评为最重要的 对SCI的人的抱怨。阿片类药物被处方以治疗Sci诱导的疼痛，即使它们有 导致卵虫类疾病的疾病，实际上可能会更严重的疼痛和延迟康复。变更 伤害感受器功能或传递疼痛的神经元被认为在SCI诱导的疼痛中起作用。我们的实验室 已经发现，小鼠的胸脊髓挫伤损伤导致发育疼痛的发展 皮肤中的行为，伤害性超敏反应，感染增加和神经病。我们的初步数据 还表明SCI在背根神经节（DRG）中引起线粒体功能障碍，这是 神经元细胞体居住。已知线粒体功能失调会导致SCI的次级 通过产生活性氧（ROS），凋亡和异常稳态，这是 最终可能导致神经元细胞死亡。综上所述，我们的数据表明遵循SCI，神经元 线粒体无法正常工作，这可能导致感染增加和神经病 以及随后的伤害感受器的超敏反应和疼痛的发展。因此，我们提议使用 小鼠SCI后的重复热处理（RHT），因为已证明这种疗法已恢复 线粒体功能，降低线粒体ROS和注射，并改善疼痛结果。我们将 还要确定在SCI的急性或慢性期间反复启动RHT是否具有不同的结果。 该提案的目标1将决定RHT对SCI诱导的疼痛，伤害感受器功能障碍和 AIM 2的神经病变将确定RHT对线粒体功能和内容的影响以及ROS 科幻之后的生产。 AIM 2还将探索是否针对线粒体特异性线粒体ROS 抗氧化剂可改善SCI的结局。我们通过恢复线粒体功能并降低来假设 RHT，伤害感受器超敏反应，神经病和疼痛的宽度炎症会减弱。博士 到目前为止，埃勒的背景和培训使她成为该奖项的有力候选人。她已经掌握了科幻 手术，现在将由两位专家Kyle Baumbauer博士和John Thyfault博士进行培训。 与分别表征伤害感受器和线粒体功能有关。她的联合官员很高 合格的科学家为Eller博士的职业发展提供了时间和资源。另外， 堪萨斯大学医学中心（KUMC）和堪萨斯城VA医疗的科学环境 中心（VAMC）将使埃勒博士不仅可以完成拟议的研究，还可以帮助她的职业生涯 发展。她将通过相关扩展自己在SCI和线粒体生物学方面的背景知识 课程工作，半小伙和会议。她将通过 在国家会议，出版手稿以及教学和心理毕业生中介绍她的作品 学生。最后，她将获取该提案中产生的数据并申请后续资金 包括VA CDA-2和NIH K01奖。埃勒博士的长期目标是将自己确立为独立 VA研究科学家和SCI疼痛专家。 CDA-1将通过允许她实现目标 她学习新的研究技术，扩大她对SCI疼痛和线粒体功能障碍的了解， 提高她的写作和演讲能力，学习如何运行成功和道德的研究计划，以及 帮助她整合到堪萨斯城VAMC。该奖项还将积极受益于VA，因为 提案涉及VA RR＆D服务的多个领域，包括非阿片类和非药物 慢性疼痛的治疗，一项分子研究，探讨了康复干预作用机制 专注于线粒体的变化，以及转化为人类受试者的潜力。