Grovola Michael R, Cullen D Kacy
Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
Center for Brain Injury & Repair, University of Pennsylvania, Philadelphia, PA 19104, USA.
Biomedicines. 2024 Sep 4;12(9):2019. doi: 10.3390/biomedicines12092019.
Traumatic brain injury (TBI) is a public health concern, with an estimated 42 million cases globally every year. The majority of TBIs are mild TBIs, also known as concussion, and result from the application of mechanical forces on the head. Most patients make a complete recovery and mortality is rare; therefore, studies investigating cellular changes after mild TBI in a clinical setting are limited. To address this constraint, our group utilized a pig model of closed-head rotational acceleration-induced TBI, which recreated the biomechanical loading parameters associated with concussion on a large gyrencephalic brain similar to humans. While our previous research has focused on immunohistochemical characterization of neuropathology, the current study utilized transcriptomic assays to evaluate an array of TBI-induced neurodegenerative analytes. Pigs subjected to mild TBI were survived for 3 days post-injury (DPI) (n = 3), 30 DPI (n = 3), or 1 year post-injury (YPI) (n = 3) and compared to animals undergoing a sham procedure (n = 8). RNA was isolated from whole coronal sections of fixed tissue and multiplexed on a Nanostring neuropathology panel. Differential expression analysis revealed 11 differentially expressed genes at 3 DPI versus sham, including downregulation of the synaptotagmin calcium sensor gene (SYT1), upregulation of the neurofibromin gene (NF1), and upregulation of the Alzheimer's disease-associated receptor gene (SORL1). There were no differentially expressed genes at 30 DPI or 1 YPI compared to shams. Additionally, high-magnitude undirected global significance scores (GSS) were detected at 3 DPI for chromatin modification and autophagy gene sets, and at 30 DPI for cytokine gene sets, while many dysregulated gene sets were highlighted by directed GSSs out to 1 YPI. This study adds to a growing body of literature on transcriptomic changes in a clinically relevant large animal model of closed-head TBI, which highlights potential therapeutic targets following mild TBI.
创伤性脑损伤（TBI）是一个公共卫生问题，全球每年估计有4200万例。大多数TBI为轻度TBI，也称为脑震荡，由头部受到机械力作用所致。大多数患者可完全康复，死亡率很低；因此，在临床环境中研究轻度TBI后细胞变化的研究有限。为解决这一限制，我们的研究小组利用了一种闭合性头部旋转加速诱导TBI的猪模型，该模型在类似于人类的大脑回脑上重现了与脑震荡相关的生物力学负荷参数。虽然我们之前的研究集中在神经病理学的免疫组织化学特征上，但当前研究利用转录组分析来评估一系列TBI诱导的神经退行性分析物。遭受轻度TBI的猪在受伤后3天（DPI）（n = 3）、30 DPI（n = 3）或受伤后1年（YPI）（n = 3）存活，并与接受假手术的动物（n = 8）进行比较。从固定组织的全冠状切片中分离RNA，并在Nanostring神经病理学面板上进行多重分析。差异表达分析显示，与假手术相比，在3 DPI时有11个差异表达基因，包括突触结合蛋白钙传感器基因（SYT1）下调、神经纤维瘤蛋白基因（NF1）上调以及阿尔茨海默病相关受体基因（SORL1）上调。与假手术相比，在30 DPI或1 YPI时没有差异表达基因。此外，在3 DPI时检测到染色质修饰和自噬基因集的高强度无向全局显著性评分（GSS），在30 DPI时检测到细胞因子基因集的GSS，而许多失调基因集在1 YPI时通过定向GSS突出显示。这项研究为关于闭合性头部TBI的临床相关大型动物模型中转录组变化的文献增添了内容，突出了轻度TBI后的潜在治疗靶点。
