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: 10341226
• 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/10341226
• 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.

推动我建立一个独立的研究企业的动力是我个人的愿望， 最大限度地恢复创伤性脑损伤（TBI）后的功能。我生活中的经历巩固了这一点 研究目标作为主要目的之一，我的职业轨迹和成就，通过逆境 它证明了我对这个目标忠诚和实现它的能力。这个使命使我 费城CMC VA医疗中心（CMC-VAMC），在那里我发现我自己的研究目标与 完全符合康复研发（RR&D）服务和我们退伍军人的需求。使 最大的影响TBI康复，我将利用一个独特的大型动物模型，以准确地复制 人体TBI的机制和表现：猪旋转加速系统应用效果显著 我的导师D凯西·卡伦博士和他的神经创伤、神经变性中心的其他研究人员， 在CMC-VAMC和宾夕法尼亚大学的修复。除了弥漫性轴索损伤， 模型导致上行网状激活系统（ARAS）受损，如在中度TBI中观察到的， 人类，导致暂时的意识丧失和对睡眠，疲劳和认知的持久影响， 从TBI中恢复的主要因素。由于它们的大脑体积很小，我们常用的啮齿动物模型 不能用于再现人体伤害的这些方面或其表现，因为损害是 旋转加速度和大脑质量的乘积在这个项目中，我建议建立在猪的模型， 延伸超过中度TBI后的急性损伤期，以建立第一个翻译模型， 在与我们的退伍军人群体最相关的长期时间点进行中度TBI康复和恢复。 这样的高保真临床前模型将提供直接测试药物的功效所必需的严格性和控制。 康复治疗的个别成分（如饮食，运动），并进行详细的机制 调查，以告知现有疗法的调整和新疗法的开发， 功效我将用一个盲法随机调查来命名这个双向翻译的容器， 膳食支链氨基酸（BCAA）治疗增强 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研究） 管理）。我们的研究将大大受益于临床相关的先进神经影像学， 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，以及具有各向异性的高分辨率死后扩散张量成像， 扩散率和纤维束成像来量化作为人类TBI的标志的脑连接的变化。我会 并利用此模型来检验定期运动康复或运动加运动的机制和效果 在六个月期间改善恢复轨迹的BCAA（也包括与退伍军人相关的延迟 治疗）。以前的研究表明，运动和BCAA疗法有共同的作用机制 因此，我将有效地测试总体假设，即增强神经营养素 信号传导和改善损伤后的睡眠质量可以改善认知恢复并减少ARAS病理 在中度创伤性脑损伤之后除了这个项目将为我们的使命提供的进步之外， 在我们的退伍军人脑损伤的功能恢复，我将收集宝贵的知识和专业知识， 来自一个专门的，世界一流的导师团队，并为我未来的职业生涯作为一个独立的VA雕刻利基 调查员由于猪模型和围绕它聚集的研究人员社区，CMC-VAMC 和宾夕法尼亚大学是TBI转化研究的中心。最好的环境， 世界上实现我的研究目标，在创伤性脑损伤康复是在这个社区，我打算成为一个 我职业生涯中不可或缺的一员我将通过这个职业发展奖实现独立 并通过富有成效的VA研究生涯提供可观的投资回报。