Detection and Mechanisms of Mild Traumatic Brain Injury

 描述（由申请人提供）：人们越来越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200万例病例。此外，越来越多的人担心，在一次mTBI后可能会有一段时间的脆弱性，在此期间，第二次mTBI可能会引起大大夸大的病理生理效应。我们已经使用了多学科的方法来产生实验性的体外和体内模型，复制mTBI在人体中的机械负荷条件。通过这些模型，我们最近发现弥漫性轴索损伤（DAI）是单次mTBI的关键病理。此外，我们已经表明，微管损伤以及钠离子通道的失调轴突创伤性损伤后的分水岭事件有助于轴突的脆弱性，功能障碍和变性。此外，我们已经产生了有希望的初步数据，表明新的神经影像学和血清生物标志物用于检测mTBI中的脑损伤的效用。在这里，我们建议使用这些模型来1）研究新的诊断技术，以评估单次和重复mTBI中的轴突病理学，以及2）探索轴突细胞骨架变化的机制作用，这些变化可能诱导增强的脆弱性，从而导致重复mTBI的损伤加剧。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）识别单次和重复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.