Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.

脑损伤康复转化模型以最大限度地恢复。

• 批准号: 10183457
• 负责人: John Charles O'Donnell
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183457
• 关键词: Acceleration; Ache; Acute; Animal Model; Animals; Anisotropy; Autopsy; Blinded; Blood; Brain; Brain Injuries; Brain Mass; Brain-Derived Neurotrophic Factor; Branched-Chain Amino Acids; Caring; Chronic; Clinical; Clinical Management; Clinical Research; Cognition; Cognitive deficits; Coma; Communities; Data; Data Collection; Diagnostic; Dietary Supplementation; Diffuse; Diffuse Axonal Injury; Diffusion Magnetic Resonance Imaging; Doctor of Philosophy; Electrophysiology (science); Enrollment; Environment; Etiology; Evaluation; Exercise; Family suidae; Fatigue; Foundations; Frequencies; Future; Gait; General Population; Goals; Head; Histopathology; Human; Immunohistochemistry; Individual; Injury; Intervention; Investigation; Investments; K-Series Research Career Programs; Knowledge; Life; Longitudinal Studies; Medical center; Mentors; Mentorship; Mission; Modeling; Monitor; Nerve Degeneration; Nervous System Trauma; Neurologic; Outcome; Output; Pathology; Pathway interactions; Patients; Pennsylvania; Phase; Philadelphia; Physical Exercise; Placebos; Pre-Clinical Model; Protocols documentation; Randomized; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Resolution; Resources; Rodent Model; Rotation; Sample Size; Serum; Services; Severities; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Slice; Structure; System; Testing; Therapeutic; Time; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Unconscious State; Unit of Measure; Universities; Veterans; actigraphy; amino acid therapy; brain size; career; clinically relevant; cognitive enhancement; cognitive recovery; cognitive testing; diet and exercise; dietary; driving force; effective therapy; efficacy testing; exercise rehabilitation; experience; improved; in vivo; interest; long-term rehabilitation; member; military veteran; multimodality; neurobehavioral; neuroimaging; neurological rehabilitation; neuroprotection; novel therapeutics; patient variability; porcine model; pre-clinical; prognostic; rehabilitation research; rehabilitation strategy; research and development; restoration; severe injury; sleep quality; therapeutic target; therapy development; tractography; translational model; treadmill; treatment group

The motivating force driving me to build an independent research enterprise has been my personal desire to maximize functional recovery after traumatic brain injury (TBI). Experiences in my life have solidified this research goal as one of primary purpose, and my career trajectory and accomplishments through adversity stand as evidence of my devotion to that purpose and ability to acheive it. This mission brought me to the Philadelphia CMC VA Medical Center (CMC-VAMC), where I have found that my own research goals align perfectly with those of the Rehabilitation R&D (RR&D) Service and the needs of our Veterans. To make the greatest impact on TBI rehabilitation, I will utilize a unique large animal model to accurately replicate the mechanisms and manifestations of human TBI: the swine rotational acceleration system applied to great effect by my mentor, D. Kacy Cullen, PhD, and other researchers in his Center for Neurotrauma, Neurodegeneration, and Restoration at the CMC-VAMC and University of Pennsylvania. In addition to diffuse axonal injury, this model results in damage to the ascending reticular activating system (ARAS) as observed in moderate TBI in humans, leading to temporary loss of consciousness and lasting effects on sleep, fatigue, and cognition that are major factors during recovery from TBI. Due to their small brain size, our commonly used rodent models cannot be used to reproduce these aspects of the human injury or their manifestations, as the damage is a product of rotational acceleration and brain mass. In this project I propose to build on the swine model, extending beyond the acute injury period following moderate TBI to establish the first translational model of moderate TBI Rehabilitation and Recovery at long-term time points most relevant for our Veteran population. Such a high-fidelity preclinical model will provide the rigor and control necessary to directly test the efficacy of individual ingredients of rehabilitation therapies (e.g. diet, exercise) and conduct detailed mechanistic investigations to inform adjustments to existing therapies and development of new therapies that improve efficacy. I will christen this vessel of bidirectional translation with a blinded, randomized investigation of the efficacy and mechanisms of action of dietary branched-chain amino acid (BCAA) therapy for enhancing cognitive recovery over a three-month study period (including investigation of Veteran-relevant delayed therapy administration). Our studies will benefit greatly from clinically-relevant advanced neuroimaging, a gamut of clinically-inspired neurobehavioral and neurological testing, extensive histopathological and immunohistochemical analyses, and high-resolution post-mortem diffusion tensor imaging with anisotropy, diffusivity, and tractography to quantify changes in brain connectivity that are a hallmark of human TBI. I will also utilize this model to test the mechanisms and efficacy of regular exercise rehabilitation or exercise plus BCAAs for improving recovery trajectory over a six-month period (also with Veteran-relevant delayed treatment). Previous studies suggest that exercise and BCAA therapies share common mechanisms of action and effects, and therefore I will effectively be testing the overarching hypothesis that enhancing neurotrophic signaling and improving sleep quality after injury can improve cognitive recovery and reduce ARAS pathology following moderate TBI. Beyond the advancements that this project will provide for our mission to maximize functional recovery from brain injury in our Veterans, I will be gathering invaluable knowledge and expertise from a dedicated, world-class mentorship team and carving a niche for my future career as an independent VA investigator. Due to the swine model and the community of researchers gathered around it, the CMC-VAMC and University of Pennsylvania are at the epicenter of translational TBI research. The greatest environment in the world to achieve my research goals in TBI rehabilitation is within this community, and I intend to become an integral member throughout my career. I will achieve independence through this Career Development Award and provide considerable return on investment through a highly productive VA research career.

推动我建立一家独立研究型企业的动力是我个人的愿望 最大限度地提高创伤性脑损伤 (TBI) 后的功能恢复。我生活中的经历证实了这一点 研究目标作为主要目的之一，以及我在逆境中的职业轨迹和成就 作为我致力于这一目标以及实现这一目标的能力的证据。这次任务让我来到了 费城 CMC VA 医疗中心 (CMC-VAMC)，我发现在那里我自己的研究目标是一致的 完全符合康复研发 (RR&D) 服务的要求以及退伍军人的需求。为了使 对TBI康复影响最大的是，我将利用独特的大型动物模型来准确地复制 人类TBI的机制和表现：猪旋转加速系统应用效果显着 由我的导师 D. Kacy Cullen 博士和他的神经创伤、神经变性中心的其他研究人员撰写， 以及 CMC-VAMC 和宾夕法尼亚大学的恢复。除了弥漫性轴突损伤外， 模型导致上行网状激活系统（ARAS）受损，正如在中度 TBI 中观察到的那样 人类，导致暂时失去意识并对睡眠、疲劳和认知产生持久影响 TBI 恢复过程中的主要因素。由于其大脑较小，我们常用的啮齿动物模型 不能用于重现人体伤害或其表现的这些方面，因为损害是 旋转加速度和脑质量的乘积。在这个项目中，我建议以猪模型为基础， 延伸至中度 TBI 后的急性损伤期之后，建立第一个转化模型 在与我们的退伍军人群体最相关的长期时间点进行适度的 TBI 康复和恢复。 这种高保真临床前模型将为直接测试疗效提供必要的严格性和控制。 康复治疗的各个组成部分（例如饮食、运动）并进行详细的机制 进行调查，以告知对现有疗法的调整和开发改善的新疗法 功效。我将通过对双向翻译的盲法随机调查来命名这个双向翻译容器。 膳食支链氨基酸（BCAA）疗法增强免疫力的功效和作用机制 三个月研究期间的认知恢复（包括对退伍军人相关延迟治疗的调查） 行政）。我们的研究将大大受益于临床相关的先进神经影像学、一系列 临床启发的神经行为和神经学测试，广泛的组织病理学和 免疫组织化学分析和具有各向异性的高分辨率死后扩散张量成像， 扩散率和纤维束描记术来量化大脑连接的变化，这是人类 TBI 的标志。我会 还利用该模型来测试定期运动康复或运动加运动的机制和功效 用于改善六个月内恢复轨迹的支链氨基酸（也包括与退伍军人相关的延迟 治疗）。先前的研究表明运动和支链氨基酸疗法具有共同的作用机制 和效果，因此我将有效地测试增强神经营养的总体假设 受伤后发出信号并改善睡眠质量可以改善认知恢复并减少 ARAS 病理 中度 TBI 后。除了该项目将为我们的使命提供的进步之外，最大限度地提高 我们的退伍军人从脑损伤中恢复功能，我将收集宝贵的知识和专业知识 来自敬业的世界级导师团队，为我未来作为一名独立退伍军人的职业生涯奠定了基础 研究者。由于猪模型和围绕它聚集的研究人员群体，CMC​​-VAMC 和宾夕法尼亚大学是转化性 TBI 研究的中心。最好的环境是 实现我在 TBI 康复方面的研究目标的世界就在这个社区内，我打算成为一名 我整个职业生涯中不可或缺的成员。我将通过这个职业发展奖实现独立 并通过高产的 VA 研究生涯提供可观的投资回报。