Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.

推动我建立一家独立研究企业的动力一直是我个人的愿望 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 将研究目标作为首要目标之一，以及我在逆境中的职业轨迹和成就 作为我对这一目标的忠诚和实现它的能力的证据。这次任务把我带到了 费城CMC VA医疗中心(CMC-VAMC)，在那里我发现我自己的研究目标是一致的 完全符合康复研发(RR&D)服务和退伍军人的需求。要使 最大的影响，我将利用一个独特的大型动物模型准确地复制 人脑损伤的机制与表现：猪旋转加速系统应用效果显著 由我的导师D·凯西·库伦博士和他的神经创伤、神经退行性变中心的其他研究人员撰写， 以及在CMC-VAMC和宾夕法尼亚大学的修复。除了弥漫性轴突损伤，这一点 模型导致上行网状激活系统(ARAS)损伤，在中度脑损伤中观察到 人类会暂时失去知觉，并对睡眠、疲劳和认知产生持久的影响 影响颅脑损伤康复的主要因素。由于它们的大脑很小，我们常用的啮齿动物模型 不能用来再现人类伤害的这些方面或其表现形式，因为损害是 旋转加速度和脑质量的乘积。在这个项目中，我建议建立在猪模型的基础上， 延缓中度颅脑损伤后急性损伤期建立首个脑损伤模型 在与我们的退伍军人人口最相关的长期时间点进行适度的TBI康复和恢复。 这种高保真的临床前模型将提供必要的严谨和控制，以直接测试 康复治疗的个别成分(例如饮食、运动)，并进行详细的机械操作 为现有疗法的调整和改善的新疗法的开发提供信息的调查 功效。我将用一项盲目的、随机的调查来命名这艘双向翻译的船 膳食支链氨基酸(BCAA)治疗增强剂的疗效及作用机制 为期三个月的认知恢复(包括对退伍军人相关延迟治疗的调查 行政管理)。我们的研究将极大地受益于临床相关的先进神经成像，一系列 临床启发的神经行为和神经测试，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， 弥散性，以及脑束成像，以量化脑连接的变化，这是人类脑损伤的标志。这就做 也利用这个模型来测试定期运动康复或运动加运动的机制和效果。 在六个月内改善复苏轨迹的BCAA(与退伍军人相关的也有延迟 治疗)。先前的研究表明，运动疗法和支链氨基酸疗法具有共同的作用机制 和效果，因此我将有效地检验增强神经营养的首要假设 损伤后信号和改善睡眠质量可以改善认知恢复和减少ARAS病理 在中度脑外伤后。除了这个项目将为我们的使命提供的进步之外，最大限度地 从我们的退伍军人脑损伤中恢复功能，我将收集宝贵的知识和专业知识 来自一支敬业的世界级导师团队，为我未来的独立退伍军人职业生涯开辟了一个利基市场 调查员。由于猪模型和聚集在它周围的研究人员社区，CMC-VAMC 和宾夕法尼亚大学都处于翻译TBI研究的中心。中国最好的环境 实现我的脑外伤康复研究目标的世界就在这个社区内，我打算成为一名 在我整个职业生涯中都是不可或缺的一员。我将通过这个职业发展奖实现独立 并通过高效的退伍军人管理局研究生涯提供可观的投资回报。

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.