Detection and Mechanisms of Mild Traumatic Brain Injury

 描述(申请人提供)：越来越多的人认识到轻度创伤性脑损伤(MTBI)或“脑震荡”是一个主要的健康问题，在美国每年有超过200万例。此外，越来越多的人担心，一次mTBI后可能会有一段时间的脆弱性，在此期间，第二次mTBI可能会导致严重夸大的病理生理效应。我们使用多学科方法建立了实验的体外和体内模型，复制了人类mTBI的机械负荷条件。通过这些模型，我们最近发现弥漫性轴索损伤(DAI)是单发mTBI的关键病理。此外，我们已经证明，创伤后微管损伤以及轴突上钠通道的调节失调是导致轴突脆弱性、功能障碍和变性的分水岭事件。此外，我们已经产生了有希望的初步数据，表明新的神经成像和血清生物标记物在检测mTBI的脑损伤方面的应用。在这里，我们建议使用这些模型来1)研究新的诊断技术来评估单发性和重复性mTBI的轴突病理，以及2)探索轴突细胞骨架变化的机制作用，这些变化可能导致易损性增加，这是重复mTBI导致损伤加剧的原因。创新：拟议研究的成功可能导致1)识别mTBI病理的新诊断标准，2)识别单一和重复mTBI的新病理和机制，以及3)揭示新的治疗靶点。

 DESCRIPTION (provided by applicant): There is a growing recognition that mild traumatic brain injury (mTBI) or "concussion" is a major health issue, with over 2 million cases each year in the United States. Moreover, there is increasing concern that there may be a period of vulnerability after one mTBI, during which time a second mTBI may induce greatly exaggerated pathophysiological effects. We have used a multidisciplinary approach to generate experimental in vitro and in vivo models that replicate the mechanical loading conditions of mTBI in humans. With these models, we have recently identified that diffuse axonal injury (DAI) is a key pathology of single mTBI. In addition, we have shown that microtubule damage as well as dysregulation of sodium channels on axons following traumatic injury are watershed events contributing to axonal vulnerability, dysfunction and degeneration. Moreover, we have generated promising preliminary data indicating the utility of novel neuroimaging and serum biomarkers for the detection of brain damage in mTBI. Here, we propose to use these models to 1) investigate novel diagnostic techniques to evaluate axonal pathology in single and repetitive mTBI, and 2) explore the mechanistic roles of axonal cytoskeletal changes that may induce enhanced vulnerability that accounts for exacerbated damage with a repeat mTBI. Innovation: Success of the proposed studies could lead to 1) new diagnostic criteria to identify mTBI pathologies, 2) identify new pathologies and mechanisms of single and repetitive mTBI, and 3) reveal new therapeutic targets.