A Fly Model of Traumatic Brain Injury

 描述（由申请人提供）：我们建议探索使用果蝇（Drosophila melanogaster）研究创伤性脑损伤（TBI）的可能性。这项研究很重要，因为TBI是一个主要的健康问题。TBI的发生率很高，每年影响美国约1/500的人，并且它与终身衰弱的身体、认知、行为和情感结果相关。这项研究也很重要，因为目前还没有治疗方法可以改善TBI的结果。自1985年以来，至少进行了21项临床试验，但没有一项显示出对TBI结局的显著益处。开发治疗的失败可能是由于TBI的复杂性，无论是在大脑损伤的严重性和空间分布方面，还是在大脑对损伤的复杂反应方面。因此，需要新的实验模型，可以帮助我们了解TBI结果的主要细胞和分子机制，并有可能确定诊断和治疗干预的新靶点。我们的苍蝇TBI模型是重要的，因为（1）它使用机械力来造成脑损伤，类似于人类中常见的机制，（2）它产生了一个连续的损伤严重程度，预测结果的严重程度，（3）它以可重复的方式产生损伤，使得有可能确定遗传和环境变量对结果的贡献，（4）它产生的损伤结果模拟了人类TBI的临床相关结果，（5）它使用了负担得起的、简单的和广泛适用的标准化实验方案，（6）它得到了对苍蝇神经系统的无与伦比的知识和可用于苍蝇的实验工具的支持。为了实现确定苍蝇和人类TBI之间的相似程度的目标，我们建议确定与TBI后死亡相关的基因和次要事件。

 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.