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.

促使我建立独立研究企业的激励力量是我个人的愿望 创伤性脑损伤（TBI）后最大化功能恢复。我一生中的经历巩固了这一点 研究目标是主要目的之一，以及我的职业轨迹和成就 作为我对这种目的的热爱和能力实现它的能力的证据。这个任务把我带到了 费城CMC VA医疗中心（CMC-VAMC），我发现自己的研究目标保持一致 完美地与康复研发（RR＆D）服务以及我们退伍军人的需求完美。做 对TBI康复的最大影响，我将利用独特的大型动物模型准确复制 人类TBI的机制和表现：猪旋转加速度系统适用于极大的效果 由我的导师D. Kacy Cullen博士和其他研究人员在他的神经变性中心，神经变性中心， 以及CMC-VAMC和宾夕法尼亚大学的恢复。除了弥散的轴突损伤， 模型会导致损坏上升的网状激活系统（ARA），如中等TBI中所观察到的 人类，导致意识的暂时丧失和对睡眠，疲劳和认知的持久影响 从TBI恢复期间的主要因素。由于它们的大脑较小，我们常用的啮齿动物模型 不能用来复制人类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产物。在这个项目中，我建议以猪模型为基础 在中度TBI之后，延伸超过急性伤害期，以建立第一个翻译模型 长期与退伍军人人口最相关的长期TBI康复和恢复。 这样的高保真临床前模型将提供直接测试功效所必需的严格和控制 康复疗法的个别成分（例如饮食，运动）并进行详细的机理 调查以告知对现有疗法的调整和开发的新疗法，以改善 功效。我将把这艘双向翻译的船thrist缩放 饮食链链氨基酸（BCAA）疗法的作用的功效和机制来增强 在三个月的研究期内认知恢复（包括研究与退伍军人相关的延迟治疗 行政）。我们的研究将从临床上与临床上的高级神经影像学中受益匪浅，这是 临床启发的神经行为和神经系统测试，广泛的组织病理学和 免疫组织化学分析和高分辨率后扩散张量成像，各向异性，各向异性， 扩散性和拖拉术，以量化人类TBI的标志大脑连通性的变化。我会 还利用该模型来测试常规运动康复或运动的机制和功效 BCAA在六个月内改善恢复轨迹的BCAA（也有与退伍军人相关的延迟 治疗）。先前的研究表明，运动和BCAA疗法具有共同的作用机制 和效果，因此我将有效地检验总体假设，即增强神经营养性 受伤后的信号传导和改善睡眠质量可以改善认知恢复并减少ARAS病理 遵循中等的TBI。除了该项目将提供我们的使命以最大化的进步之外 从我们的退伍军人中，我将获得宝贵的知识和专业知识 来自一个敬业的世界一流的指导团队，并为我作为独立VA的未来职业雕刻一个利基市场 研究者。由于猪模型和研究人员的社区围绕它，CMC-VAMC 宾夕法尼亚大学是转化TBI研究的中心。最伟大的环境 实现我在TBI康复中的研究目标的世界在这个社区内，我打算成为一个 在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 并通过高效的VA研究职业提供可观的投资回报。