Molecular Mechanisms and Treatment of Diffuse Axonal Injury

项目摘要 这项新的研究人员提案描述了一项为期五年的培训计划，以培养一名医生- 研究创伤性脑损伤的科学家生涯。这位研究人员获得了神经生物学博士学位。 重点介绍弥漫性轴索损伤(DAI)的机制和神经炎性反应。这位调查员 完成神经外科实习，在儿童神经外科和儿童脊柱畸形方面获得两项奖学金， 目前是宾夕法尼亚大学的临床讲师。在进行拟议的研究时， 首席研究员将获得蛋白质生物化学、基因敲除基因组学、行为研究、 以及先进的神经成像技术。道格拉斯·史密斯博士，教授兼研究主席 神经外科，将指导首席研究员的科学发展。忠告 由全国公认的杰出科学家组成的委员会将提供科学和职业建议。这个 宾夕法尼亚大学神经外科致力于提供理想的环境和 确保首席调查员成功的资源。研究方案和环境将允许 首席调查员，发展学术事业，成为神经创伤社区的领导者。 研究将集中在无髓鞘轴突节段对启动机制的选择性易损性 弥漫性脑损伤的研究以及克服DAI病理生物学的治疗策略。DAI病机进展 通过一系列导致延迟性或继发性轴突切断的事件。这创造了一个治疗窗口 在此期间，治疗可以减轻或防止轴突断开。DAI细胞骨架损伤机制的研究进展 人们对此仍然知之甚少，也没有治疗方法。该提案旨在确定准确的DAI启动 基因，解释细胞骨架蛋白在轴突损伤中的作用，并研究两种神经保护 减轻DAI病理生物学的范例。利用实验性弥漫性脑损伤小鼠模型，特定的目的是 包括：1.)确定兰维尔轴突起始段和/或结节是否是二次轴突切断术的部位 其次是弥漫性脑损伤和2。)确定血影蛋白在弥漫性脑损伤后继发性轴索切断中的作用 TBI。这项提议将第一次检验这样一种假设，即在兴奋的时候破坏血影蛋白细胞质 沿着轴突的区域是损伤的病灶。神经保护范例包括保存 血影蛋白通过外源性和内源性抑制细胞骨架中的钙蛋白酶，从而靶向 用于降解的幽灵蛋白。拟议的研究将提高我们对DAI介导的细胞骨架的理解 损伤和测试旨在防止继发性轴突切断的神经保护策略。组织学的整合， 行为结果和先进的神经成像技术将创建一个预测损伤严重程度的模型 并预测弥漫性脑损伤后的康复。

Project Summary This new investigator proposal describes a five-year training program for the development of a physician- scientist career studying traumatic brain injury (TBI). This investigator completed a Ph.D. in neurobiology focused on mechanisms and neuroinflammatory responses to diffuse axonal injury (DAI). This investigator completed neurosurgery residency, two fellowships in pediatric neurosurgery and pediatric spinal deformity, and is currently a Clinical Instructor at the University of Pennsylvania. In carrying out the proposed research, the principle investigator will acquire expertise in protein biochemistry, knockout genomics, behavioral studies, and advanced neuroimaging techniques. Dr. Douglas Smith, Professor and Chair of Research in the Department of Neurosurgery, will mentor the principle investigator's scientific development. An advisory committee of outstanding, nationally recognized scientists will provide scientific and career advice. The Department of Neurosurgery at the University of Pennsylvania is committed to providing an ideal setting and resources to ensure the principle investigator's success. The research proposal and environment will allow the principle investigator to develop an academic career and become a leader in the neurotrauma community. Research will focus on the selective vulnerability of unmyelinated axon segments to initiating mechanisms of diffuse TBI as well as treatment strategies to overcome DAI pathobiology. DAI pathogenesis proceeds through a cascade of events leading to delayed or secondary axotomy. This creates a therapeutic window during which treatments may mitigate or prevent axon disconnection. Mechanisms of DAI cytoskeletal injury remain poorly understood and there are no treatments. The proposal seeks to determine precise DAI initiating loci, explain the cytoskeletal protein spectrin's role in axonal injury, and investigate two neuroprotective paradigms to mitigate DAI pathobiology. Using an experimental diffuse TBI murine model, the Specific Aims include: 1.) Determine if the axon initial segment and/or nodes of Ranvier are sites of secondary axotomy following diffuse TBI and 2.) Determine spectrin-mediated contributions to secondary axotomy following diffuse TBI. This proposal will be the first to test the hypothesis that disruption of the spectrin cytosketeton at excitable domains along the axon serves as a nidus for injury. Neuroprotective paradigms include preservation of the spectrin cytoskeleton through exogenous and endogenous inhibition of the protease calpain, which targets spectrin for degradation. The proposed research will improve our understanding of DAI-mediated cytoskeletal injury and test neuroprotective strategies designed to prevent secondary axotomy. The integration of histology, behavioral outcomes, and advanced neuroimaging techniques will create a model that predicts injury severity and prognosticates recovery after diffuse brain injury.