MTBI Biomarkers

这个核心的主要目标是识别一组可在人类血清中测量的替代蛋白标记物， 结合其他临床因素，可预测轻度脑外伤后的长期功能障碍。第二个目标是 使用轴突变性的替代标记物促进对潜在分子机制和 为本提案中使用的实验模型提供进一步的验证。到目前为止，还没有单独的标记 始终证明有能力预测轻度脑外伤后的长期功能损害。要确定 新的脑损伤标记物并开发了标记物小组，我的实验室启动了第一个全球蛋白质分析 从退化的神经元中释放出来。我们鉴定了14-3-3(3，14-3-3^，一种低磷化形式的 神经细丝H，a-Spectrin的钙蛋白酶裂解产物和asectrin的caspase裂解产物 作为从死亡神经元释放的高度丰富的神经元丰富的蛋白质。这一点的有效性 通过对脑外伤或脑损伤后脑脊液和血清中这些蛋白的免疫检测，建立了一种方法 大鼠的缺血，以及严重的脑外伤或手术导致的人类循环停止。要扩展这一点 对轻度人类脑外伤的研究，其核心的具体目的是：(1)确定代孕对象之间的关系 神经细胞培养模型中标志蛋白释放、钠通道功能障碍和轴突变性 轴突损伤(项目3)；(2)在轻度脑损伤的猪模型中分析我们的新的替代标志物面板，并描述 轴突组织病理学和钠通道功能障碍的变化(项目2)；(3)评估血清升高 在轻度人类脑损伤中使用相同的标记板，并将其与认知、神经和 功能障碍的放射测量(项目1)。一种基于替代标记物的轻症预后评估方法 脑损伤，加上一种评估实验性神经保护疗法的简单量化手段，将 对轻型颅脑损伤的管理和治疗具有巨大的益处。

The main goal of this core is to identify a panel of surrogate protein markers measurable in human serum that, in combination with other clinical factors, predicts long-term dysfunction following mild TBI. A second goal is to use surrogate markers for axonal degeneration to promote studies of the underlying molecular mechanisms and provide further validation for experimental models used in this proposal. Thus far, no individual marker has consistently demonstrated the ability to predict long-term functional impairment following mild TBI. To identify new markers for TBI and develop a marker panel, my laboratory initiated the first global analysis of protein release from degenerating neurons. We identified 14-3-3(3, 14-3-3^, a hypophpsphorylated form of neurofilament H, a calpain-derived cleavage product of a-spectrin, and a caspase cleavage product of aspectrin as highly abundant neuron-enriched proteins released from dying neurons. The validity of this approach was established by immunodetection of these proteins in CSF and serum following TBI or cerebral ischemia in rats, as well as severe TBI or surgically-induced circulation arrest in humans. To extend this research to mild human TBI, the specific aims of the core are to: (1) determine relationships between surrogate marker protein release, sodium channel dysfunction and axonal degeneration in a neuronal culture model for axonal injury (Project 3); (2) analyze our novel surrogate marker panel in a pig model of mild TBI, and relate changes to axonal histopathology and sodium channel dysfunction (Project 2); (3) evaluate serum elevations for the same marker panel in mild human TBI, and compare their levels with cognitive, neurological, and radiological measures of dysfunction (Project 1). A surrogate marker-based method for the prognosis of mild TBI, along with a simple quantitative means of assessing experimental neuroprotective therapies, would have enormous benefit for the management and treatment of mild TBI.