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: 10727616
• 负责人: Brian J. Kelley
• 金额: $ 21.89万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-18 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727616
• 关键词: 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; Ensure; Environment; Event; Experimental Models; Fellowship; Future; Genomics; Histologic; Histology; Injury; Knock-out; Knockout Mice; Mediating; Mentors; Methods; Microtubules; Mind; Molecular; 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; Vertebral column; axon injury; behavioral outcome; behavioral study; calpastatin; career; demographics; design; effective therapy; effectiveness evaluation; fluid percussion injury; improved; improved outcome; insight; instructor; mouse model; neurofilament; neuroimaging; neuroinflammation; neuron loss; neuronal cell body; neuroprotection; neurosurgery; novel; overexpression; predictive modeling; preservation; prevent; professor; prognostication; 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 这项新的研究者提案描述了一项为期五年的医生培养培训计划- 研究创伤性脑损伤（TBI）的科学家。该研究者完成了博士学位。神经生物学 着重于弥漫性轴索损伤（DAI）的机制和神经炎症反应。本研究者 完成了神经外科住院医师培训，获得了小儿神经外科和小儿脊柱畸形的两项奖学金， 目前是宾夕法尼亚大学的临床讲师。在进行拟议的研究时， 主要研究人员将获得蛋白质生物化学，敲除基因组学，行为研究， 和先进的神经成像技术道格拉斯史密斯博士，教授和研究主席， 神经外科，将指导主要研究者的科学发展。一个咨询 由杰出的、国家认可的科学家组成的委员会将提供科学和职业建议。的 宾夕法尼亚大学神经外科系致力于提供一个理想的环境， 确保主要研究人员的成功。研究方案和环境将允许 首席研究员发展学术生涯，并成为神经创伤社区的领导者。 研究将集中在无髓鞘轴突段的选择性脆弱性启动机制 弥漫性TBI以及克服DAI病理学的治疗策略。DAI发病机制进展 通过一系列事件导致延迟或继发性轴突切断。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 仍然知之甚少，也没有治疗方法。该提案旨在确定精确的DAI启动 基因座，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性 减轻DAI病理生物学的范例。使用实验性弥漫性TBI小鼠模型， 包括：1.）确定轴突起始段和/或郎维氏结是否为继发性轴突切断部位 在弥漫性TBI之后，和2.）确定血影蛋白介导的继发性轴突切断的作用 创伤性脑损伤这一提议将是第一个测试这一假设的，即在兴奋性细胞分裂素的破坏。 沿着轴突的结构域作为损伤的病灶。神经保护的范例包括保护神经元的功能。 血影蛋白细胞骨架通过外源性和内源性抑制蛋白酶钙蛋白酶，其目标 血影蛋白降解。这项研究将提高我们对DAI介导的细胞骨架蛋白的理解。 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模型，预测损伤的严重程度 并促进弥漫性脑损伤后的恢复。