Biological Inquiry into the Mechanisms and Neuroprotective Strategy for TBI

项目总结/摘要 创伤性脑损伤（TBI）是一个严重的健康问题，也是一个潜在的灾难性的衰弱医疗问题。 预后不良的紧急情况和长期残疾的可能性。爆炸相关和闭头 在战区发生的创伤性脑损伤中，受伤占大多数。最近的研究表明， 弥漫性轴索损伤（DAI）是最常见的病理特征， TBI的表现。因此，TBI诊断和治疗的未来进展取决于我们的 了解DAI的颞叶轴突病理生理学及其在患者预后中的作用。但几 这些因素限制了我们对DAI的病理和功能意义的理解：（1）DAI是一种 非常难以非侵入性地检测;（2）它在几小时到几天，甚至几个月的过程中发展， 损伤;（3）DAI难以研究，因为它涉及多种类型的神经元，并且是弥漫性和多灶性的， 出现在深层和皮层下的白色物质中。 这项研究计划将利用视神经系统来探讨假设， 创新神经保护和再生方法有效地将轴突损伤最小化， 改善中枢神经系统损伤后的形态和功能恢复。视神经负责传递 从眼睛到大脑的视觉信息，包含来自单个神经元群体的轴突， 视网膜神经节细胞它的外围位置使其在结构上和 功能上。视神经损伤，造成轴突损伤，形态学上与 大脑提供了一个定义明确的解剖系统，消除了许多与 大脑实验此外，利用先进的小鼠遗传技术，成功全长 在出生后的小鼠中已经实现了从眼睛到大脑的视神经再生。研究 证明了限制TBI后DAI和治疗脑创伤的可行性。 目的：探讨脑梗死后神经元轴突损伤，尤其是DAI的病理及机制。 冲击力诱导的TBI（bTBI），并开发新的治疗方法，本研究计划提出了3个具体目标： 目的1明确创伤和/或创伤后神经元轴突损伤的病理和机制， 创伤性脑损伤Aim 2将使用先进的小鼠遗传技术来阐明导致 慢性轴突损伤目的3将评估一种新的神经保护和再生方法，以减少 创伤导致轴突损伤。神经元和轴突损伤的定量将使用 免疫组织化学、分子和生物化学测定的标准方案， 很好的。如果这一假设被证明是有效的，那么一项创新技术将对 在不久的将来可以将其转化为临床实践。

Project Summary/Abstract Traumatic brain injury (TBI) is a significant health problem and a potentially catastrophic debilitating medical emergency with a poor prognosis and the possibility of long-term disability. Blast-related and closed-head injuries constitute the majority of TBIs occurring in the combat zone. Recent studies demonstrate that diffuse axonal injury (DAI) is the most common pathologic feature largely accounting for the clinical manifestations of TBI. Thus, future advancements in the diagnosis and treatment of TBI depend on our understanding of temporal axonal pathophysiology of DAI and its role in patient outcome. However, several factors have limited our understanding of the pathology and functional implications of DAI: (1) DAI is extremely difficult to detect noninvasively; (2) it develops over a course of hours to days, even months, after injury; (3) DAI is difficult to study because it involves multiple types of neurons and is diffuse and multifocal, appearing throughout the deep and subcortical white matter. This research project will take advantage of the optic nerve system to explore the hypothesis that an innovative neuroprotective and regenerative approach is effective on minimizing axonal damage and improving the morphological and functional recovery after CNS trauma. The optic nerve, which conveys visual information from the eye to brain, contains axons originated from a single neuronal population- retinal ganglion cells. Its peripheral location makes it an unusually accessible both structurally and functionally. Optic nerve injury that creates axonal damage morphologically identical to that seen in the brain offers a well-defined anatomical system that obviates many of the difficulties associated with experiments on the brain. Moreover, using the advanced mouse genetic technology, successful full-length optic nerve regeneration from the eye to the brain has been achieved in postnatal mice. The study demonstrates the feasibility of limiting DAI following TBI and treating brain trauma. To elucidate the pathology and mechanisms associated with axonal damage, especially DAI resulted from blast force-induced TBI (bTBI), and to develop new treatment, this research plan proposes 3 specific aims: Aim 1 is proposed to define the pathology and mechanisms of axonal damage induced by trauma and/or TBI. Aim 2 will use advanced mouse genetic technology to elucidate the molecular signals leading to the chronic axonal damage. Aim 3 will evaluate a novel neuroprotective and regenerative approach to minimize axonal damage resulted from trauma. Quantification of neuron and axon damage will be carried out using the standard protocols of immunohistochemistry and molecular and biochemical assays that have been well-established. If the hypothesis is proven valid, an innovative technology that has strong implications for translation into clinical practice could be developed in the near future.