The Role of Epigenetics in Mitochondrial Biogenesis-Mediated Recovery after Spinal Cord Injury

表观遗传学在脊髓损伤后线粒体生物发生介导的恢复中的作用

• 批准号: 10216171
• 负责人: Natalie E Scholpa
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216171
• 关键词: ADRB2 gene; Address; Adrenergic Agonists; Affect; Age; Agonist; Antioxidants; Area; Behavioral; Biogenesis; Bioinformatics; Biology; Blood Vessels; Caring; Cell physiology; Clinical; Clinical Trials; Communication; Complex; Data; Development; Development Plans; Devices; Disease; Doctor of Philosophy; Epigenetic Process; Event; Exposure to; FDA approved; Female; Financial compensation; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health Care Costs; Healthcare; Healthcare Systems; Human; Individual; Injury; Intensive Care; Investigation; Knowledge; Laboratories; Lesion; Locomotor Recovery; Maintenance; Mediating; Mediator of activation protein; Medical; Mentors; Mitochondria; Modification; Molecular; Mus; Nature; Neurosurgeon; Oral; Oxygen; Pathology; Patients; Pharmacology; Phase; Play; Publishing; Recovery; Rehabilitation therapy; Reporting; Research Personnel; Role; Site; Spinal Cord; Spinal cord injury; Therapeutic; Time; Training; Trauma; United States; United States Department of Veterans Affairs; Veterans; beta-2 Adrenergic Receptors; career; career development; clinical application; cost; disability; educational atmosphere; epigenome; experience; formoterol; improved; in vivo; injury recovery; innovation; loss of function; male; mitochondrial dysfunction; novel strategies; prevent; service member; skills; therapeutic target; treatment group

The goal of this project is to determine the role of epigenetic modifications of mitochondrial genes in the induction of the plateau phase after spinal cord injury (SCI), and to exploit these modifications to promote recovery. SCI is a devastating disorder often resulting in loss of function below the injury site. In recent years, service members have been threatened by more advanced warfare, such as improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. The devastating and debilitating nature of these injuries has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. Improved therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the VA healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Thus far, the majority of studies targeting mitochondrial dysfunction following SCI have focused on downstream aspects of mitochondrial function (e.g. antioxidant defenses). Reestablishment of mitochondrial function through pharmacological induction of mitochondrial biogenesis (MB) remains an underexplored but novel strategy. I previously reported that treatment with the mitochondrially biogenic FDA-approved β2-adrenergic receptor agonist formoterol beginning up to 8h after SCI improves spinal cord mitochondrial function, decreases lesion volume and enhances locomotor recovery by 7 days post-injury (DPI). Consistent with other published data, the majority of the improvements observed with formoterol occurred within the first 2 weeks, after which recovery plateaued. A similar effect is observed in humans, with the majority of recovery taking place within the first year then reaching a plateau. The mechanism behind the development of this plateau phase, however, is not fully understood. By determining the mechanism of its formation, the plateau phase could be prevented and/or reversed, potentially allowing for continued recovery following injury. My preliminary studies revealed genetic differences within the injured spinal cord of formoterol-treated mice between the recovery phase (7 DPI) and the plateau phase (15 DPI), namely a decrease in genes associated with mitochondrial function, and a concurrent increase in genes associated with epigenetic modifications. Therefore, I hypothesize that epigenetic alterations contribute to decreased transcription of mitochondrial genes within the spinal cord during the plateau phase, preventing continued recovery of mitochondrial function and limiting the efficacy of formoterol treatment in mice. To address this hypothesis, I propose the following Specific Aims: 1) Further elucidate the genetic profile within the spinal cord during the post-SCI recovery period (7 DPI) and plateau phase (≥15 DPI), with and without formoterol treatment in mice; 2) Elucidate the mechanisms of epigenetic modifications on the transcription of mitochondrial genes during the transition from recovery to plateau phase post-SCI, with and without formoterol treatment; 3) Assess the pharmacological efficacy of inhibiting epigenetic events on MB and recovery post-SCI in vivo, with and without formoterol treatment. Successful completion of this proposal could provide integral information into the recovery plateau observed after SCI. I am using an FDA-approved compound, male and female mice and initiating treatment up to 8h after injury, emphasizing the clinical applicability. This proposal will also directly assess the therapeutic potential of my findings by determining if modulation of epigenetic status improves recovery after injury. My mentoring team has formulated a comprehensive career development plan that includes exposure to a rich educational environment, opportunities to improve oral and written communication skills and mentoring on project and laboratory maintenance to ease transition to independence. This project and training will facilitate the completion of my long-term career goal of becoming and independent VA researcher.

该项目的目标是确定线粒体基因的表观遗传修饰在 脊髓损伤（SCI）后平台期的诱导，并利用这些修改 促进康复 SCI 是一种破坏性的疾病，通常会导致损伤部位以下的功能丧失。 多年来，军人一直受到更先进的战争的威胁，例如简易爆炸物 设备，最终导致更严重和更复杂的伤害，包括 SCI。 这些伤害的性质并没有减轻，退伍军人事务部 (VA) 是最大的医疗保健部门。 SCI 患者网络，为美国 25% 的受害者提供护理。 治疗 SCI 的疗法不仅使患者受益，而且使 VA 医疗保健系统受益。 SCI 的定义是对脊髓的直接创伤，这会破坏脉管系统，导致氧气减少 迄今为止，该区域内的递送并降低了线粒体维持细胞能量的能力。 大多数针对 SCI 后线粒体功能障碍的研究都集中在下游方面 线粒体功能（例如抗氧化防御）通过重建线粒体功能。 线粒体生物发生（MB）的药理学诱导仍然是一种尚未充分探索但新颖的策略。 我之前报道过，使用 FDA 批准的线粒体生物源 β2 肾上腺素受体进行治疗 SCI 后 8 小时内开始使用激动剂福莫特罗可改善脊髓线粒体功能，减少病变 体积并增强受伤后 7 天的运动恢复 (DPI)，与其他已发表的数据一致。 使用福莫特罗观察到的大部分改善发生在前两周内，之后恢复 在人类中观察到类似的效果，大部分恢复发生在第一年内。 然而，这个平台期发展背后的机制并不完全清楚。 通过确定其形成机制，可以防止和/或平台期。 逆转，可能允许受伤后继续恢复 我的初步研究表明遗传。 接受福莫特罗治疗的小鼠损伤脊髓在恢复期（7 DPI）和恢复期（7 DPI）之间的差异 平台期（15 DPI），即与线粒体功能相关的基因减少，同时 与表观遗传修饰相关的基因增加因此，我为表观遗传而奋斗。 改变导致脊髓内线粒体基因转录减少 平台期，阻止线粒体功能的持续恢复并限制其功效 为了解决这一假设，我提出以下具体目标：1）进一步 阐明 SCI 后恢复期 (7 DPI) 和平台期脊髓内的遗传图谱 (≥15 DPI)，对小鼠进行或不进行福莫特罗治疗；2) 阐明表观遗传机制； 从恢复期到平台期过渡期间线粒体基因转录的改变 SCI后，有或没有福莫特罗治疗；3) 评估抑制表观遗传的药理学功效； 在有或没有福莫特罗治疗的情况下，体内MB和SCI后恢复的事件。 该提案的成功完成可以为观察到的恢复平台提供完整的信息 SCI 后，我使用 FDA 批准的化合物，对雄性和雌性小鼠进行治疗，并在 8 小时内开始治疗。 损伤，强调临床适用性，该提案还将直接评估其治疗潜力。 我的发现是通过确定表观遗传状态的调节是否可以改善受伤后的恢复。 我的指导团队制定了全面的职业发展计划，其中包括接触丰富的人才 教育环境、提高口头和书面沟通技巧的机会以及指导 项目和实验室维护，以方便向独立的过渡。该项目和培训将促进。 完成我成为独立 VA 研究员的长期职业目标。