Molecular Mechanisms and Treatment of Diffuse Axonal Injury

弥漫性轴突损伤的分子机制和治疗

• 批准号: 9892622
• 负责人: Brian J. Kelley
• 金额: $ 15.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892622
• 关键词: Address; Advisory Committees; Affect; Algorithms; Antibodies; Axon; Axotomy; Biomechanics; Calpain; Childhood; Clinical; Collaborations; Communities; Cytoskeletal Proteins; Cytoskeleton; Deformity; Development; Diffuse; Diffuse Axonal Injury; Diffuse Brain Injury; Doctor of Philosophy; Effectiveness; Ensure; Environment; Event; Experimental Models; Fellowship; Future; Genomics; Histologic; Histology; Injury; Knock-out; Knockout Mice; Lead; Mediating; Mentors; Methods; Microtubules; Mind; Molecular; Molecular Structure; Morbidity - disease rate; Myelin; Nature; Nervous System Trauma; Neurobiology; Neuronal Plasticity; Neurons; Nodal; Outcome; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Patients; Pennsylvania; Peptide Hydrolases; Physicians; Population; Positioning Attribute; Program Development; Protein Biochemistry; Protein Subunits; Public Health; Ranvier' s Nodes; Recovery; Rehabilitation therapy; Research; Research Personnel; Research Proposals; Residencies; Resources; Role; Scientist; Secondary to; Severities; Shapes; Site; Spectrin; Spinal; Structural Protein; Techniques; Testing; Therapeutic; Training Programs; Trauma; Traumatic Brain Injury; Universities; axon injury; base; behavioral outcome; behavioral study; calpastatin; career; demographics; design; effective therapy; fluid percussion injury; improved; improved outcome; injured; insight; instructor; mouse model; neurofilament; neuroimaging; neuroinflammation; neuron loss; neuronal cell body; neurosurgery; novel; overexpression; predictive modeling; preservation; prevent; professor; protein structure; response; success; theories; therapy design; treatment strategy

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.

项目概要 这项新的研究者提案描述了一个为期五年的医生发展培训计划—— 研究创伤性脑损伤（TBI）的科学家职业生涯。这位研究人员完成了博士学位。在神经生物学中 专注于弥漫性轴突损伤（DAI）的机制和神经炎症反应。这位调查员 完成了神经外科住院医师实习、两项儿科神经外科和儿科脊柱畸形研究金， 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、行为研究等方面的专业知识， 和先进的神经影像技术。道格拉斯·史密斯博士，教授兼研究主席 神经外科将指导主要研究者的科学发展。咨询 由国家认可的杰出科学家组成的委员会将提供科学和职业建议。这 宾夕法尼亚大学神经外科致力于提供理想的环境和 确保主要研究者成功的资源。研究计划和环境将允许 首席研究员发展学术生涯并成为神经创伤界的领导者。 研究将集中于无髓鞘轴突片段对启动机制的选择性脆弱性 弥漫性 TBI 的研究以及克服 DAI 病理学的治疗策略。 DAI 发病机制进展 通过一系列导致延迟或继发性轴索切断术的事件。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 细胞骨架损伤的机制 人们对此仍知之甚少，也没有治疗方法。该提案旨在确定 DAI 的精确启动 位点，解释细胞骨架蛋白血影蛋白在轴突损伤中的作用，并研究两种神经保护作用 减轻 DAI 病理学的范例。使用实验性弥漫性 TBI 小鼠模型，具体目标 包括： 1.) 确定轴突初始段和/或 Ranvier 节点是否是二次轴切术的部位 弥漫性 TBI 后和 2.) 确定弥漫性 TBI 后血影蛋白介导的二次轴切术的贡献 创伤性脑损伤。该提案将是第一个检验以下假设的假设：血影蛋白细胞骨架在兴奋时被破坏。 轴突沿线的区域是损伤的病灶。神经保护范例包括保存 通过外源性和内源性抑制蛋白酶钙蛋白酶来形成血影蛋白细胞骨架，该蛋白酶的目标是 血影蛋白降解。拟议的研究将提高我们对 DAI 介导的细胞骨架的理解 损伤并测试旨在防止继发性轴索切断术的神经保护策略。组织学的整合， 行为结果和先进的神经影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恢复。