A Fly Model of Traumatic Brain Injury

 描述(申请人提供)：我们建议探索使用果蝇(果蝇)来研究创伤性脑损伤(TBI)的可能性。这项研究很重要，因为脑外伤是一个主要的健康问题。脑外伤的发病率很高，每年在美国每500人中就有1人受到影响，它与终身衰弱的身体、认知、行为和情绪结果有关。这项研究也很重要，因为目前还没有可用的治疗方法来改善脑外伤的预后。自1985年以来，至少进行了21项临床试验，没有一项临床试验显示对脑外伤的结果有显著的益处。未能开发治疗方法可能是由于脑外伤的复杂性，无论是就脑损伤的严重程度和空间分布而言，还是就脑损伤对损伤的复杂反应而言。因此，需要新的实验模型来帮助我们理解脑外伤预后的主要细胞和分子机制，并有可能为诊断和治疗干预确定新的靶点。我们的飞行脑损伤模型意义重大，因为(1)它使用机械力来造成脑损伤，类似于人类通常发生的机制，(2)它产生一系列损伤严重程度来预测结果严重程度，(3)它以可重复的方式产生损伤，使确定遗传和环境变量对结果的贡献成为可能，(4)它产生的损伤结果模拟人类脑损伤的临床相关结果，(5)它使用负担得起、简单且广泛适用的标准化实验方案，(6)它得到了苍蝇神经系统的无与伦比的知识和苍蝇可用的实验工具的支持。为了实现确定苍蝇和人类脑外伤之间的相似程度的目标，我们建议识别与脑外伤后死亡相关的基因和继发性事件。

 DESCRIPTION (provided by applicant): We propose to explore the possibility of using fruit flies (Drosophila melanogaster) to study traumatic brain injury (TBI). This research is important because TBI is a major health problem. TBI occurs with high incidence, annually affecting about 1 in 500 people in the U.S., and it is associated with lifelong debilitating physical, cognitive, behavioral, and emotional outcomes. This research is also important because there are no therapies currently available to improve TBI outcomes. Since 1985, at least 21 clinical trials have been conducted, and none have shown a significant benefit in TBI outcomes. The failure to develop therapies is likely due to the complexity of TBI, both in terms of the severity and spatial distribution of injury to the brain and the elaborate responses of the brain to injury. Therefore, there is a need for new experimental models that can help us understand the main cellular and molecular mechanisms that underlie TBI outcomes, with the potential for identifying novel targets for diagnostic and therapeutic intervention. Our fly TBI model is significant because (1) it uses a mechanical force to inflict brain injury, similar to mechanisms that commonly occur in humans, (2) it generates a continuum of injury severity that predicts outcome severity, (3) it generates injury in a reproducible manner, making it possible to determine the contribution of genetic and environmental variables to outcomes, (4) it produces injury outcomes that mimic clinically relevant outcomes of TBI in humans, (5) it uses standardized experimental protocols that are affordable, simple, and widely applicable, and (6) it is supported by the unparalleled knowledge of the fly nervous system and experimental tools that are available for flies. To achieve the goal of determining the extent of similarity between fly and human TBI, we propose to identify genes and secondary events associated with death following TBI.