Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
Gen Physiol Biophys. 2021 Nov;40(6):523-539. doi: 10.4149/gpb_2021038.
Discovering novel diagnostic biomarkers and signatures for traumatic brain injury (TBI) represents a major challenge in the brain trauma research. Detailed analysis of post-concussive molecular pathways based on experimental data could provide a new insight into the pathophysiological sequelae and mapping of recovery mechanisms involved in TBI. MicroRNAs (miRNAs) detectable in peripheral body fluids after TBI are promising carriers of this missing knowledge. In order to define the signature of peripheral miRNAs signaling associated with mild TBI (mTBI), we performed a comprehensive meta-analysis of miRNA profiles in mTBI patients using multiple curated pathway databases. Using a bioinformatic pipeline with integrated data analysis we identified a set of genes that are connected to deregulated circulating miRNAs following the mTBI. Identified genes belong to specific pathways of MAPK, TGF-β, WNT, TLR2/4, PI3K/AKT, insulin, and growth factor signaling. Since the enriched pathways markedly overlap among the various biological fluids, signaling associated with mTBI that is concomitantly reflected in serum, plasma and saliva is robust and unique. Furthermore, we identified a network of 33 validated interacting proteins and their regulatory miRNAs that link the post-mTBI signaling in peripheral fluids with neurodegeneration-associated interaction pathways. Presented data provide a comprehensive insight into molecular events following mTBI, and the top predicted genes represent a group of novel candidate targets to be validated in connection with mTBI.
发现创伤性脑损伤 (TBI) 的新型诊断生物标志物和特征是脑创伤研究中的主要挑战。基于实验数据对脑震荡后分子途径进行详细分析,可以深入了解 TBI 涉及的病理生理后果和恢复机制。TBI 后可在周围体液中检测到的 microRNAs (miRNAs) 是这种缺失知识的有前途的载体。为了确定与轻度创伤性脑损伤 (mTBI) 相关的外周 miRNA 信号特征,我们使用多个经过精心整理的途径数据库对 mTBI 患者的 miRNA 图谱进行了全面的荟萃分析。使用具有集成数据分析的生物信息学管道,我们确定了一组与 mTBI 后循环 miRNAs 失调相关的基因。鉴定的基因属于 MAPK、TGF-β、WNT、TLR2/4、PI3K/AKT、胰岛素和生长因子信号通路的特定途径。由于丰富的途径在各种生物流体中明显重叠,因此在血清、血浆和唾液中同时反映出与 mTBI 相关的信号是稳健且独特的。此外,我们确定了一个由 33 个经过验证的相互作用蛋白及其调节 miRNA 组成的网络,该网络将外周液中 post-mTBI 信号与神经退行性变相关的相互作用途径联系起来。呈现的数据提供了对 mTBI 后分子事件的全面了解,并且预测的顶级基因代表了一组与 mTBI 相关的新型候选靶标。