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

据估计，脊髓损伤(SCI)患者中有42,000人是退伍军人，这增加了 退伍军人事务部(VA)的重大医疗负担，因为脊髓损伤导致许多长期 并发症。慢性疼痛是一种长期的并发症，通常被认为是最严重的 脊髓损伤患者的个人投诉。阿片类药物是用来治疗脊髓损伤引起的疼痛的，尽管它们有 导致阿片类药物滥用障碍，实际上会加剧疼痛和推迟康复。中的更改 伤害性感受器功能，即传递疼痛的神经元，被认为在脊髓损伤引起的疼痛中发挥作用。我们的实验室 已发现小鼠胸椎挫伤会导致自发性疼痛 行为、伤害性感受器过敏、炎症增加和皮肤神经病变。我们的初步数据 也提示脊髓损伤导致背根神经节(DRG)线粒体功能障碍，这是 神经元胞体存在。已知功能障碍的线粒体参与了脊髓损伤的第二阶段。 通过产生活性氧(ROS)、细胞凋亡和异常的钙稳态， 最终会导致神经细胞死亡。综上所述，我们的数据表明，在脊髓损伤后，神经元 线粒体功能不正常，这可能会增加炎症和神经病变 以及随后出现的伤害性感受器过敏和疼痛。因此，我们建议使用 小鼠脊髓损伤后的重复热处理(RHT)，因为这种疗法已经被证明可以恢复 线粒体功能，减少线粒体ROS和炎症，并改善疼痛结果。我们会 还要确定在SCI急性期或慢性期开始重复的RHT是否会有不同的结果。 该提案的目标1将确定RHT对脊髓损伤引起的疼痛、伤害性感受器功能障碍的影响，以及 神经病变，而Aim 2将确定RHT对线粒体功能和内容以及ROS的影响 SCI之后的制作。Aim 2还将探索是否以线粒体特异性ROS为靶点 抗氧化剂可改善脊髓损伤的预后。我们假设通过恢复线粒体功能和减少 RHT引起的广泛炎症、伤害性感受器超敏反应、神经病变和疼痛将会减轻。Dr。 到目前为止，埃勒的背景和训练使她成为这一奖项的有力候选人。她已经掌握了SCI 现在将由两位专家凯尔·鲍姆鲍尔博士和约翰·蒂费斯博士进行技术培训 分别与伤害性感受器和线粒体功能的特征有关。她的合作导师们高度重视 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， 堪萨斯大学医学中心(KUMC)和堪萨斯城退伍军人管理局的科学环境 中心(VAMC)将允许埃勒博士不仅完成拟议的研究，还将帮助她的职业生涯 发展。她将扩大她在脊髓损伤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她的演示、写作和指导技能 在全国会议上发表她的作品，出版手稿，教授和指导毕业生 学生们。最后，她将利用这项提案产生的数据，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让自己成为一名独立的 退伍军人事务部研究科学家和脊髓损伤疼痛专家。CDA-1将通过允许 她需要学习新的研究技术，扩大她对脊髓损伤疼痛和线粒体功能障碍的了解， 提高她的写作和演示技能，学习如何运行一个成功的、符合道德的研究项目，以及 帮助她融入堪萨斯城VAMC。这一奖项也将使退伍军人管理局积极受益，因为 提案涉及退伍军人管理局RR&D服务的多个领域，包括非阿片类药物和非药理学 慢性疼痛的治疗，一项探讨康复干预作用机制的分子研究 专注于线粒体的变化，以及转化为人类受试者的可能性。

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.