Kurowski Brad G, Treble-Barna Amery, Pitzer Alexis J, Wade Shari L, Martin Lisa J, Chima Ranjit S, Jegga Anil
1 Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine , Cincinnati, Ohio.
2 Division of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
J Neurotrauma. 2017 Jul 15;34(14):2280-2290. doi: 10.1089/neu.2016.4856. Epub 2017 May 3.
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, and cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall, this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.
创伤性脑损伤（TBI）是全球发病和死亡的主要原因之一。它与许多医学、神经学、认知和行为后遗症相关。基因因素对TBI后的生物学及相关恢复的影响尚不清楚。旨在阐明基因影响对TBI后神经恢复作用的研究将有助于更好地实现预后个体化，并为目前严重缺乏的新治疗方法的开发提供依据。目前与TBI相关的基因研究主要集中在特定的候选基因上。本研究的目的是使用基于系统生物学的方法，识别那些在TBI后临床结局中先前涉及的基因变异所过度代表的生物学过程，并识别可能与TBI后恢复相关的独特基因。在进行系统综述以确定文献中与临床结局相关的基因后，我们使用所识别的基因进行基于系统生物学的综合计算分析，以确定分子成分之间的相互作用，并建立参与TBI恢复的基因调控和功能模型。分析确定基因变异主要在两个生物学过程中过度代表：对损伤的反应（细胞增殖、细胞死亡、炎症反应和细胞代谢）以及神经认知和行为储备（大脑发育、认知和行为）。总体而言，本研究证明了使用基于系统生物学的方法来识别对恢复过程重要的独特/新基因或基因集。基于这种系统生物学方法的研究结果为基因变异对TBI恢复重要的潜在复杂生物学过程的潜在影响提供了更多见解，并可能为TBI的实证基因相关研究的发展提供依据。TBI需要未来结合系统生物学方法与基因组、蛋白质组和表观遗传学方法的研究。
