Functional three dimensional brain-like tissues to study mechanisms of traumatic brain injury

 描述(由申请人提供)：对创伤引起的脑损伤机制有很大的洞察力。不同类型的头部创伤造成的损害，从局灶性挫伤到脑震荡，都需要对方法和结果进行新的思考，以提供治疗窗口，以缓解这一对儿童和成人的主要风险，以及新的预防措施。为了满足这一主要和不断增长的需求，我们计划利用体外新的3D类脑组织，结合动物研究，将损伤和反应的标志和机制联系起来。我们的假设是，具有模拟活体条件的结构和功能特征的3D小鼠和人脑组织将为研究脑功能和对机械损伤的反应提供生理相关的读数，以研究参与创伤性脑损伤和修复的机制。这种相关性将为了解损伤激活的通路、损伤类型如何影响不同的通路、大脑如何对这些不同的通路做出反应提供新的重要见解，并帮助确定干预和治疗的新线索。体外3D组织(啮齿动物和人类)与体内啮齿动物研究的结合，受到不同类型的损伤(例如，惯性和体重下降)的影响，将提供对以前没有追求的结果的全面评估，同时还提高了翻译相关性。维持结构和功能数月的组织模型的可用性允许对结果进行急性和慢性评估(遗传、生化、代谢组学、电生理)。这些读数将提供前所未有的洞察力和对这些类型伤害的因果关系的解释。我们最初对 机制，如涉及Akt和mTOR的激活，将为进一步研究提供合适的起点，而转录组学将允许识别新的线索。最终，比较体外和体内模型之间的转录组反应，以及计划中的其他读数，并在体外和体内的急性和慢性时间反应中这样做，应该会为损伤影响和干预模式提供前所未有的新见解。所有这些计划都有大量的初步数据支持。

 DESCRIPTION (provided by applicant): There is a significant need for new insights into mechanisms of brain damage due to trauma. Damage due to different types of head trauma, from focal contusions to concussions, requires new thinking about methods and outcomes to provide windows for treatment to ameliorate this major risk to children and adults, as well new preventative measures. To address this major and growing need we plan to utilize novel 3D brain-like tissues in vitro, coupled with animal studies, to correlate markers and mechanisms of injury and response. Our hypothesis is that 3D mouse and human brain-like tissues with structural and functional features mimicking in vivo conditions will provide physiologically-relevant readouts for the study of brain function and responses to mechanical damage to study mechanisms involved in traumatic brain injury and repair. Such correlations will provide new and important insight into pathways activated by injury, how the type of injury effects different pathways, how the brain heals in response to these different pathways, and to help identify new leads for intervention and treatments. The coupling of in vitro 3D tissues (rodent and human) with in vivo rodent studies, impacted by different types of damage (e.g., inertial and weight drop), will provide a comprehensive assessment of outcomes not previously pursued, while also improving translational relevance. The availability of tissue models that sustain structure and function for months allows for both acute and chronic assessments of outcomes (genetic, biochemical, metabolomics, electrophysiological). These readouts will offer unprecedented insight and interpretation of cause and effect to these types of injuries. Our initial insight into mechanisms, such as involving Akt and mTOR activation, will provide suitable starting points for further study, while transcriptomics will allow for the identification of new leads. Ultimately, comparing transcriptome responses between the in vitro and in vivo models, along with the other readouts planned, and doing so in both acute and chronic temporal responses in vitro and in vivo, should provide unprecedented new insight into damage effects and modes for intervention. All of the plans are supported with extensive preliminary data.