Proteomic identification of plasma TBI biomarkers

描述(由申请人提供)： 创伤性脑损伤(TBI)是美国年轻人死亡和残疾的主要原因，2003-2007年间，军事卫生系统记录了超过43,779名脑损伤患者。对于脑外伤患者的护理来说，一个关键的问题是缺乏能够告知治疗方案、治疗反应和预后的血液生物标志物。一种简单的血液蛋白仪表板的开发将彻底改变患者的分类和管理。好了！利用人类群体识别生物标志物的研究受到患者和损伤异质性(患者人口统计学、损伤严重程度和采样时间)与样本量关系的问题的困扰。此外，直到最近，同时评估多个推定标记的能力在技术上是不可能的。好了！为了解决这些问题，我们对脑外伤的小鼠模型进行了蛋白质组学分析，控制了损伤后的严重程度和分析时间。此外，我们正在通过分析APOE转基因小鼠的血浆蛋白来最大限度地检测损伤差异反应的标记物，这些转基因小鼠模拟了我们和其他人在人类群体中报告的损伤后有利(APOE3)或不利(APOE4)结果。随后，将进一步研究对损伤有显著反应的血浆蛋白与运动功能、认知表现和神经病理变化的关系。与颅脑损伤结果测量相关的蛋白质随后将被用于在人类VA脑损伤患者群体中进行研究和验证。好了！这项提案的目标是验证一组供临床医生使用的血浆生物标记物，以指导他们对脑外伤的评估、治疗和管理。已识别的生物标志物也可能作为治疗干预措施的替代结果衡量标准，并可能为新的治疗策略提供候选靶点。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading cause of death and disability among young Americans in the United States, and the Military Health System recorded over 43,779 TBI patients in 2003-2007. A critical problem for the care of the TBI patient is the paucity of blood biomarkers that can inform treatment options, response to treatment and prognosis. The development of a simple blood protein panel will revolutionize patient triage and management. ! Studies to identify biomarkers using human populations are beset by problems of patient and injury heterogeneity (patient demographics, injury severity and time to sampling) in relationship to sample size. Furthermore, until recently, the ability to assess multiple putative markers simultaneously was not technologically possible. ! To address these problems we have undertaken proteomic analysis in a mouse model of TBI, controlling for severity and analysis time post injury. Moreover, we are maximizing our ability to detect markers of differential response to injury by analyzing the plasma proteins in APOE transgenic mice which model the favorable (APOE3) or unfavorable (APOE4) outcome after injury that we and others have reported in human populations. Plasma proteins showing a significant response to injury will then be further investigated in relation to motor function, cognitive performance and neuropathological changes. Proteins which correlate with TBI outcome measures will then be targeted for investigation and validation in a human VA TBI patient population. ! The goal of this proposal is to validate a panel of plasma biomarkers for use by clinicians to guide their assessment, treatment and management of TBI. The identified biomarkers may also have value as surrogate outcome measures of treatment interventions, and may provide candidate targets for novel therapeutic strategies.