Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model
Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model
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DOI：
10.1089/neu.2011.1789
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发表时间：
2012-01-20
影响因子：
4.2
通讯作者：
Mullan, Michael
中科院分区：
文献类型：
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作者：
Crawford, Fiona;Crynen, Gogce;Mullan, Michael
目前缺乏创伤性脑损伤（TBI）的诊断和预后生物标志物，使患者的治疗和管理变得混乱，并且随着TBI人群的增长而日益受到关注。我们已经从通过在1.3 mm或1.8 mm深度的受控皮质撞击接受TBI的小鼠中产生了血浆蛋白质组谱，将这些与假损伤动物的血浆蛋白质组谱进行比较，以鉴定损伤后24小时、1个月或3个月时对轻度或重度TBI特异的血浆生物标志物。为了确定可能的预后生物标志物，我们使用了载脂蛋白E（APOE）3和APOE4转基因小鼠，它们在TBI后分别表现出相对有利和不利的结果。使用定量蛋白质组学方法（用于相对和绝对定量的同量异序标记-iTRAQ），我们已经鉴定了作为TBI的函数以及响应于TBI * APOE基因型相互作用而显著调节的蛋白质，后者代表潜在的预后生物标志物。这些初步数据清楚地表明血浆蛋白变化不仅是损伤依赖性的，而且是相互作用依赖性的。重要的是，这些结果表明在3个月的时间点存在TBI依赖性和相互作用依赖性血浆蛋白，这在小鼠模型中是损伤后相当长的时间，并且对于在损伤后延长的时间段接受评估的战斗退伍军人可能具有重要意义。此外，我们对功能相关蛋白质簇的鉴定表明了特定生物模块的干扰，这可能会增加它们的价值，超出单独的生物标志物的价值。
The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.8 mm depth, comparing these against those of sham injured-animals to identify plasma biomarkers specific to mild or severe TBI at 24 hours, 1 month, or 3 months post-injury. To identify possible prognostic biomarkers, we used apolipoprotein E (APOE)3 and APOE4 transgenic mice, which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI. Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation - iTRAQ) we have identified proteins that are significantly modulated as a function of TBI and also in response to the TBI*APOE genotype interaction, the latter representing potential prognostic biomarkers. These preliminary data clearly demonstrate plasma protein changes that are not only injury dependent but also interaction dependent. Importantly, these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3-month time point, which is a considerable time post-injury in the mouse model, and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury. Furthermore, our identification of clusters of functionally related proteins indicates disturbance of particular biological modules, which potentially increases their value beyond that of solitary biomarkers.