Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS One. 2011;6(8):e23111. doi: 10.1371/journal.pone.0023111. Epub 2011 Aug 11.
Experimental evidence suggests that random, spontaneous (stochastic) fluctuations in gene expression have important biological consequences, including determination of cell fate and phenotypic variation within isogenic populations. We propose that fluctuations in gene expression represent a valuable tool to explore therapeutic strategies for patients who have suffered traumatic brain injury (TBI), for which there is no effective drug therapy. We have studied the effects of TBI on the hippocampus because TBI survivors commonly suffer cognitive problems that are associated with hippocampal damage. In our previous studies we separated dying and surviving hippocampal neurons by laser capture microdissection and observed unexplainable variations in post-TBI gene expression, even though dying and surviving neurons were adjacent and morphologically identical. We hypothesized that, in hippocampal neurons that subsequently are subjected to TBI, randomly increased pre-TBI expression of genes that are associated with neuroprotection predisposes neurons to survival; conversely, randomly decreased expression of these genes predisposes neurons to death. Thus, to identify genes that are associated with endogenous neuroprotection, we performed a comparative, high-resolution transcriptome analysis of dying and surviving hippocampal neurons in rats subjected to TBI. We found that surviving hippocampal neurons express a distinct molecular signature--increased expression of networks of genes that are associated with regeneration, cellular reprogramming, development, and synaptic plasticity. In dying neurons we found decreased expression of genes in those networks. Based on these data, we propose a hypothetical model in which hippocampal neuronal survival is determined by a rheostat that adds injury-induced genomic signals to expression of pro-survival genes, which pre-TBI varies randomly and spontaneously from neuron to neuron. We suggest that pharmacotherapeutic strategies that co-activate multiple survival signals and enhance self-repair mechanisms have the potential to shift the cell survival rheostat to favor survival and therefore improve functional outcome after TBI.
实验证据表明，基因表达的随机、自发（随机）波动具有重要的生物学后果，包括细胞命运的决定和同基因群体内的表型变异。我们提出，基因表达的波动代表了一种有价值的工具，可以探索遭受创伤性脑损伤（TBI）的患者的治疗策略，而目前尚无有效的药物治疗方法。我们研究了 TBI 对海马体的影响，因为 TBI 幸存者通常会遭受与海马体损伤相关的认知问题。在我们之前的研究中，我们通过激光捕获显微解剖术分离了死亡和存活的海马神经元，并观察到 TBI 后基因表达的无法解释的变化，尽管死亡和存活的神经元相邻且形态相同。我们假设，在随后受到 TBI 的海马神经元中，与神经保护相关的基因的预先 TBI 表达随机增加，使神经元更容易存活；相反，这些基因的随机表达减少使神经元更容易死亡。因此，为了确定与内源性神经保护相关的基因，我们对 TBI 大鼠死亡和存活的海马神经元进行了比较、高分辨率转录组分析。我们发现，存活的海马神经元表达了一个独特的分子特征——与再生、细胞重编程、发育和突触可塑性相关的基因网络表达增加。在死亡的神经元中，我们发现这些网络中的基因表达减少。基于这些数据，我们提出了一个假设模型，其中海马神经元的存活是由一个变阻器决定的，该变阻器将损伤诱导的基因组信号添加到存活基因的表达中，而存活基因的表达在神经元之间随机自发地变化。我们建议，同时激活多个存活信号并增强自我修复机制的药物治疗策略有可能将细胞存活变阻器移向有利于存活的方向，从而改善 TBI 后的功能结果。
