Neurotrauma especially traumatic brain injury (TBI) is the leading cause of death and disability worldwide. To improve upon the early diagnosis and develop precision-targeted therapies for TBI, it is critical to understand the underlying molecular mechanisms and signaling pathways. The transcription factor, nuclear factor kappa B (NFκB), which is ubiquitously expressed, plays a crucial role in the normal cell survival, proliferation, differentiation, function, as well as in disease states like neuroinflammation and neurodegeneration. Here, we hypothesized that real-time noninvasive bioluminescence molecular imaging allows rapid and precise monitoring of TBI-induced immediate and rapid spatio-temporal activation of NFκB signaling pathway in response to Glia maturation factor (GMF) upregulation which in turn leads to neuroinflammation and neurodegeneration post-TBI. To test and validate our hypothesis and to gain novel mechanistic insights, we subjected NFκB-RE-Luc transgenic male and female mice to TBI and performed real-time noninvasive bioluminescence imaging (BLI) as well as photoacoustic and ultrasound imaging (PAI). Our BLI data revealed that TBI leads to an immediate and sustained activation of NFκB signaling. Further, our BLI data suggest that especially in male NFκB-RE-Luc transgenic mice subjected to TBI, in addition to brain, there is widespread activation of NFκB signaling in multiple organs. However, in the case of the female NFκB-RE-Luc transgenic mice, TBI induces a very specific and localized activation of NFκB signaling in the brain. Further, our microRNA data suggest that TBI induces significant upregulation of mir-9-5p, mir-21a-5p, mir-34a-5p, mir-16-3p, as well as mir-155-5p within 24 h and these microRNAs can be successfully used as TBI-specific biomarkers. To the best of our knowledge, this is one of the first and unique study of its kind to report immediate and sustained activation of NFκB signaling post-TBI in a gender-specific manner by utilizing real-time non-invasive BLI and PAI in NFκB-RE-Luc transgenic mice. Our study will prove immensely beneficial to gain novel mechanistic insights underlying TBI, unravel novel therapeutic targets, as well as enable us to monitor in real-time the response to innovative TBI-specific precision-targeted gene and stem cell-based precision medicine.

神经外伤，尤其是创伤性脑损伤 (TBI) 是全世界死亡和残疾的主要原因。为了改善 TBI 的早期诊断并开发精准靶向疗法，了解潜在的分子机制和信号通路至关重要。转录因子核因子 kappa B (NFκB) 广泛表达，在正常细胞存活、增殖、分化、功能以及神经炎症和神经变性等疾病状态中发挥着至关重要的作用。在这里，我们假设实时无创生物发光分子成像可以快速、精确地监测 TBI 诱导的 NFκB 信号通路的即时和快速时空激活，以响应神经胶质成熟因子 (GMF) 上调，进而导致神经炎症和神经退行性变TBI 后。为了测试和验证我们的假设并获得新的机制见解，我们对 NFκB-RE-Luc 转基因雄性和雌性小鼠进行 TBI，并进行实时无创生物发光成像 (BLI) 以及光声和超声成像 (PAI)。我们的 BLI 数据显示，TBI 会导致 NFκB 信号传导立即持续激活。此外，我们的 BLI 数据表明，特别是在遭受 TBI 的雄性 NFκB-RE-Luc 转基因小鼠中，除了大脑之外，多个器官中 NFκB 信号传导也广泛激活。然而，对于雌性 NFκB-RE-Luc 转基因小鼠来说，TBI 会诱导大脑中 NFκB 信号传导的非常特异性和局部激活。此外，我们的 microRNA 数据表明，TBI 在 24 小时内诱导 mir-9-5p、mir-21a-5p、mir-34a-5p、mir-16-3p 以及 mir-155-5p 显着上调，并且这些 microRNA可以成功地用作 TBI 特异性生物标志物。据我们所知，这是同类中第一个也是独特的研究之一，通过利用 NFκB 中的实时非侵入性 BLI 和 PAI，以性别特异性方式报告 TBI 后 NFκB 信号传导的立即和持续激活-RE-Luc转基因小鼠。我们的研究将证明非常有利于获得 TBI 背后的新机制见解，揭示新的治疗靶点，并使我们能够实时监测创新 TBI 特异性精准靶向基因和基于干细胞的精准医学的反应。