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

 描述（由申请人提供）：对创伤所致脑损伤机制的新见解有着重要的需求。从局灶性挫伤到脑震荡，不同类型的头部创伤造成的损伤需要对方法和结果进行新的思考，以提供治疗窗口，减轻儿童和成人的这一主要风险，以及新的预防措施。为了解决这一主要和不断增长的需求，我们计划利用新型的体外3D脑样组织，结合动物研究，将损伤和反应的标记物和机制联系起来。我们的假设是，具有模拟体内条件的结构和功能特征的3D小鼠和人脑样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，以研究创伤性脑损伤和修复中涉及的机制。这种相关性将为损伤激活的通路提供新的重要见解，损伤类型如何影响不同的通路，大脑如何响应这些不同的通路进行愈合，并帮助确定新的干预和治疗线索。体外3D组织（啮齿动物和人类）与体内啮齿动物研究的耦合，受不同类型损伤（例如，惯性和重量下降），将提供以前没有追求的结果的全面评估，同时也提高了翻译的相关性。可持续数月的结构和功能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、生物化学、代谢组学、电生理学）。这些读数将提供前所未有的洞察力和解释的原因和影响，这些类型的伤害。我们最初对 机制，如涉及Akt和mTOR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。最后，比较体外和体内模型之间的转录组反应，沿着其他计划的读数，并在体外和体内的急性和慢性时间反应中这样做，应该提供前所未有的新的损伤效应和干预模式的见解。所有这些计划都得到了广泛的初步数据的支持。

 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.