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.

项目摘要 这项新的调查员建议描述了一项为期五年的培训计划，以开发医生 - 研究创伤性脑损伤的科学家职业（TBI）。这位调查员完成了博士学位。在神经生物学中 专注于机制和对弥漫性轴突损伤（DAI）的神经炎症反应。这个调查员 完成神经外科居住，小儿神经外科和小儿脊柱畸形的两个研究金， 目前是宾夕法尼亚大学的临床讲师。在进行拟议的研究时， 原则研究者将获得蛋白质生物化学，基因敲除基因组学，行为研究的专业知识， 和先进的神经影像学技术。道格拉斯·史密斯（Douglas Smith）博士，教授兼研究主席 神经外科部将指导主要研究者的科学发展。咨询 杰出的，全国认可的科学家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系致力于提供理想的环境和 确保主要研究者成功的资源。研究建议和环境将允许 主要研究人员发展学术职业并成为神经劳玛社区的领导者。 研究将重点放在不髓鞘的轴突段的选择性脆弱性上，以启动机制 弥漫性TBI以及克服DAI病理生物学的治疗策略。 DAI发病机理进行 通过一系列导致延迟或继发轴切开术的事件。这会创建一个治疗窗口 在此过程中可以减轻或防止轴突断开。 DAI细胞骨架损伤的机制 保持不足，没有治疗。该提案旨在确定确切的DAI启动 基因座，解释细胞骨架蛋白质谱在轴突损伤中的作用，并研究两个神经保护作用 减轻DAI病理生物学的范例。使用实验性弥漫性TBI鼠模型，具体目的 包括：1。）确定轴突初始段和/或兰维尔的节点是否是次级轴切开术的位置 弥漫性TBI和2。）确定频谱弥漫后对次级轴切开术的贡献 TBI。该提案将是第一个检验假设的假设，即在可激发时扰动Spectrin cytosketeton 沿轴突沿线的结构域用作损伤的Nidus。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的谱细胞骨架，该蛋白酶钙蛋白酶的靶向 降解的频谱。拟议的研究将提高我们对DAI介导的细胞骨架的理解 旨在预防继发轴切开术的损伤和测试神经保护策略。组织学的整合， 行为结果和高级神经影像学技术将创建一个预测伤害严重程度的模型 并预测弥漫性脑损伤后恢复。