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.

据估计，脊髓损伤（SCI）患者中有42，000人是退伍军人， 严重的医疗保健负担退伍军人事务部（VA）作为SCI的结果，在许多长期 并发症一个长期的并发症是慢性疼痛，这通常是最重要的 对SCI患者的投诉。阿片类药物是用来治疗SCI引起的疼痛的，尽管它们 导致阿片类药物滥用障碍，实际上会加重疼痛并延迟康复。变化 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。我们实验室 发现小鼠胸椎挫伤导致自发性疼痛的发展 行为、伤害感受器超敏反应、炎症增加和皮肤神经病变。我们的初步数据 也表明脊髓损伤导致背根神经节（DRG）线粒体功能障碍，这是脊髓损伤的原因。 神经元细胞体驻留。功能障碍的线粒体是已知的，有助于脊髓损伤的第二阶段 通过产生活性氧（ROS）、细胞凋亡和异常钙稳态， 最终会导致神经细胞死亡总之，我们的数据表明，在SCI后，神经元 线粒体功能不正常，这可能导致炎症和神经病变增加 以及随后的伤害感受器超敏反应和疼痛的发展。因此，我们建议使用 在小鼠SCI后重复热处理（rHT），因为这种疗法已被证明可以恢复 本发明的组合物还可用于改善线粒体功能，减少线粒体ROS和炎症，并改善疼痛结果。我们将 还确定在SCI的急性期或慢性期开始重复rHT是否具有不同的结果。 本提案的目的1将确定rHT对SCI诱导的疼痛、伤害感受器功能障碍和 而Aim 2将确定rHT对线粒体功能和含量以及ROS的影响 生产后，SCI。目的2还将探索是否用线粒体特异性靶向线粒体ROS， 抗氧化剂改善SCI的结果。我们假设，通过恢复线粒体功能， 具有rHT的广泛炎症、伤害感受器超敏反应、神经病和疼痛将被减弱。博士 埃勒的背景和培训，迄今使她成为一个强有力的候选人，这个奖项。她已经掌握了SCI 手术，现在将由两位专家，凯尔鲍姆鲍尔博士和约翰Thyfault博士，在技术培训 分别与表征伤害感受器和线粒体功能相关。她的导师们 为埃勒博士的职业发展投入时间和资源的合格科学家。此外该 堪萨斯大学医学中心（KUMC）和堪萨斯城退伍军人管理局医学中心的科学环境 中心（VAMC）将允许埃勒博士不仅完成拟议的研究，但也在她的职业生涯援助 发展她将扩大她的SCI和线粒体生物学的背景知识，通过相关的 课程作业、研讨会和会议。她将通过以下方式提高自己的演讲、写作和指导技能： 在全国性会议上展示她的作品，出版手稿，教学和指导研究生 学生最后，她会拿着这个提案产生的数据，申请后续的资助 包括VA CDA-2和NIH K 01奖。埃勒博士的长期目标是建立自己作为一个独立的 VA研究科学家和SCI疼痛专家。CDA-1将帮助她实现目标， 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知识， 提高她的写作和演讲技巧，学习如何运行一个成功的和道德的研究计划， 帮助她融入堪萨斯城的VAMC这一奖项也将有利于VA，因为 提案涉及VA RR&D服务的多个领域，包括非阿片类药物和非药物 治疗慢性疼痛，一项分子研究，探索康复干预的作用机制， 重点是线粒体的变化，以及转化为人类受试者的潜力。