MTBI Biomarkers

该核心的主要目标是鉴定一组在人血清中可测量的替代蛋白标志物， 结合其他临床因素，可预测轻度TBI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，以促进对潜在分子机制的研究， 进一步验证本提案中使用的实验模型。到目前为止，还没有一个标记 一致地证明了预测轻度TBI后长期功能障碍的能力。以识别 为了开发TBI的新标记物并开发标记物组，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）， 神经丝H、α-血影蛋白的钙蛋白酶衍生的裂解产物和Aspectrin的半胱天冬酶裂解产物 从垂死的神经元中释放出来的富含神经元的蛋白质。的有效性 通过免疫检测TBI或脑损伤后CSF和血清中这些蛋白， 在大鼠中的缺血，以及在人类中的严重TBI或药物诱导的循环停滞。延长本 针对轻度TBI的研究，其核心的具体目标是：（1）确定替代物之间的关系 标记蛋白释放、钠通道功能障碍和轴突变性， 轴突损伤（项目3）;（2）在轻度TBI的猪模型中分析我们的新替代标记物组，并将其与 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TBI患者中使用相同的标记物组，并将其水平与认知、神经和 功能障碍的放射学测量（项目1）。一种基于替代标志物的轻症预后评估方法 创伤性脑损伤，沿着一种简单的定量评估实验性神经保护治疗的方法， 对于轻度TBI的管理和治疗有巨大的益处。

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.