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首页> 外文会议>ASMS Conference on Mass Spectrometry and Allied Topics >PROTEOMICS ANALYSIS OF THE CEREBRAL CORTEX AFTER FEAR CONDITIONING STRESS AND ACUTE BLAST OVERPRESSURE INDICATE ALTERED METABOLISM AND CONVERGENCE UPON NEURODEGENERATIVE AND BRAIN-DYSTROPHIN PATHWAYS.
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PROTEOMICS ANALYSIS OF THE CEREBRAL CORTEX AFTER FEAR CONDITIONING STRESS AND ACUTE BLAST OVERPRESSURE INDICATE ALTERED METABOLISM AND CONVERGENCE UPON NEURODEGENERATIVE AND BRAIN-DYSTROPHIN PATHWAYS.

机译：恐惧调节应激和急性爆破过压后脑皮质的蛋白质组学分析表明神经退行和脑 - 营养不良素途径的代谢和收敛性改变。

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Introduction. Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) remain serious medical issues for active duty service members and veterans. Although mTBI and PTSD are highly co-morbid in these populations, little is known about their underlying brain molecular mechanisms. Defining global protein and pathway changes that occur in the injured brain is critical to understanding mechanisms of injury and may lead to identifying molecular based targets of therapy. This preliminary study characterizes changes in the rodent cerebral cortex proteome defined by label-free mass spectrometry with multi-platform data integration in animals exposed to conditioned fear and/or blast over-pressure (BOP). Methods. Using male Sprague-Dawley rats, inescapable electric shock (IES) and repetitive blast over-pressure (75kPa BOP/day X 3 days) were used as models of stress or mTBI, respectively (Genovese et. al, 2013). Experimental groups were: (1) sham IES + sham BOP (SS), (2) IES + sham BOP (IS), (3) sham IES + BOP (SB), and (4) IES + BOP (IB). Cerebral cortex peptides were generated by in-gel tryptic digest and analyzed by nLCMS/ MS on a Thermo LTQ Velos. Searches and peptide assembly were performed using Sequest with Scaffold (SQ-SCF) or Myrimatch with IDPicker (MM-IDP). Spectral count statistical significance was determined using Prism software (Student's t-Test, p ≤ 0.05 vs. Sham). All Uniprot entries were manually inspected and converted into Unigene entries. Decoy proteins were removed. For all proteins identified within the rat cerebral cortex proteome (all proteins and all treatments) by MM-IDP and SQ-SCF, Protein identifications that were shared among MM-IDP and SQ-SCF were determined using Biovenn. Enriched biological processes, molecular functions, and cellular components of this core proteome were determined using Webgestalt using the rat genome as a reference set and the hypergeometric test for enrichment analysis (Benjamini-Hochberg, p<0.05 and a minimum of 2 proteins were accepted per category). Categories are displayed as the ratio of enrichment "R". Proteins that expressed differential abundance after IS, SB, or IB compared to SS based on spectral count significance in MM-IDP or SQ-SCF were analyzed by Biovenn to determine which proteins were common to both search-assembly platforms. Thereafter, direct-proteinprotein interaction and gene set enrichment (GSEA) for key biological processes and disease associations were determined using Pathway Studio Web. Select proteins were confirmed by peptide MRM-MS or Western blotting. Preliminary Data. Significant fold changes of each experimental group were highly conserved among the two platforms. IES alone had the greatest effect on the proteome and led to altered abundance of 50 proteins. Thirty-one proteins were affected by r- BOP alone, and just 14 proteins were differentially abundant in cohorts exposed to IES followed by r-BOP. All three treatment groups mapped to pathways involved in metabolism or to neurodegenerative diseases and disorders (e.g. Alzheimer's disease or epilepsy). Surprisingly, proteins with altered abundance in all three treatment groups were involved in Duchenne muscular dystrophy and dystrophin signaling pathways, for which abundance of several proteins was confirmed with multiple reaction monitoringmass spectrometry (MRM-MS) or western blotting. Novel Aspect. The first study to use multi-platform, label-free strategies to characterize the brain proteome in models relevant to fear conditioning and blast overpressure. Proteomics uncovered previously unforeseen proteins, interactions, and convergent pathways within the cerebral cortex. These results may serve as novel biomarkers of acute exposure to adverse psychological and physical trauma. Further, proteomicsbased discovery may have far reaching effects upon diagnoses and treatment of both PTSD and mTBI, co-morbid conditions.
机译：介绍。轻度创伤性脑损伤（MTBI）和创伤后应激障碍（PTSD）仍然是现役服务成员和退伍军人的严重医疗问题。虽然MTBI和PTSD在这些群体中具有高度持续的态度，但对其潜在的脑部分子机制知之甚少。在受伤大脑中定义出现的全球蛋白质和途径变化对于了解损伤机制至关重要，并且可能导致识别基于分子的治疗目标。该初步研究表征了由无标记的质谱法定义的啮齿动物脑皮质蛋白质组的变化，其在暴露于调节恐惧和/或爆破过压（BOP）的动物中的多平台数据集成。方法。使用雄性Sprague-Dawley大鼠，不可避免的电击（IE）和重复爆破过压（75kPa Bop / Day x 3天）分别作为压力或MTBI的模型（Genovese等。Al，2013）。实验组是：（1）假iES +假BOP（SS），（2）IES +假BOP（IS），（3）假iES + BOP（SB），和（4）IES + BOP（IB）。通过凝胶胰蛋白酶消化产生脑皮质肽，并通过NLCMS / MS在Thermo LTQ Velos上分析。使用与Idpicker（MM-IDP）的序列（SQ-SCF）或MyRimatch常用进行搜索和肽组件。使用棱镜软件（学生的T-Test，P≤0.05Vs.Shem）确定光谱计数统计学意义。所有UNIPROT条目都被手动检查并转换为UNIGENE条目。除去诱饵蛋白。对于通过MM-IDP和SQ-SCF在大鼠脑皮质蛋白质组（所有蛋白质和所有治疗中）鉴定的所有蛋白质，使用BioCoCO确定MM-IDP和SQ-SCF之间共享的蛋白质鉴定。使用大鼠基因组作为参考组测定该核心蛋白质的富集的生物学方法，分子函数和细胞组分，并且每次接受富集分析的超高度试验（本Jamini-Hochberg，P <0.05和至少2个蛋白质）类别）。类别显示为富集“R”的比率。通过基于MM-IDP或SQ-SCF的光谱计数意义进行了表达差异丰度的蛋白质，Sb或Ib被Bi-IDP或SQ-SCF进行了分析，以确定哪些蛋白质在搜索组装平台上是共同的。此后，使用途径工作室网确定用于关键生物学过程和疾病关联的直接蛋白质蛋白相互作用和基因设定富集（GSEA）。通过肽MRM-MS或蛋白质印迹确认选择蛋白质。初步数据。两个平台之间的每个实验组的显着折叠变化很高。仅IES对蛋白质组产生了最大的影响，并导致改变了50种蛋白质的丰富。单独的R-BOP影响了三十一种蛋白质，只有14个蛋白质在暴露于IES的群组中差异丰富，然后是R-BOP。所有三个治疗组都映射到参与代谢的途径或神经变性疾病和疾病（例如阿尔茨海默病或癫痫）。令人惊讶的是，所有三个治疗组中具有改变的丰度的蛋白质涉及Duchenne肌营养不良症和营养不良的信号传导途径，其中多种反应监测谱图（MRM-MS）或Western印迹确认了多种蛋白质的丰度。新方面。第一次使用多平台，无标签策略的研究表征与恐惧调节和爆炸超压相关的模型中的脑蛋白质。蛋白质组学发现以前未经保留的蛋白质，相互作用和脑皮质内的收敛途径。这些结果可作为急性暴露于不良心理和物理创伤的新型生物标志物。此外，在诊断和治疗PTSD和MTBI，共同病态条件下，蛋白质组学基础的发现可能具有深远的效果。

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