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

功能性三维类脑组织用于研究创伤性脑损伤的机制

• 批准号: 9266832
• 负责人: DAVID L. KAPLAN
• 金额: $ 35.55万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266832
• 关键词: Acceleration; Acute; Address; Adult; Adverse effects; Animals; Anxiety; Astrocytes; Biochemical; Blood - brain barrier anatomy; Brain; Brain Concussion; Brain Injuries; Candidate Disease Gene; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Child; Chronic; Clinical Trials; Closed head injuries; Cognitive; Cognitive deficits; Contusions; Cortical Contusions; Coupled; Coupling; Craniocerebral Trauma; Data; Deceleration; Dimensions; Drops; Electrophysiology (science); Epidemic; FRAP1 gene; Functional disorder; Gene Deletion; Gene-Modified; Genetic; Goals; Histology; Hour; Human; Impaired cognition; In Vitro; Individual; Injectable; Injury; Interleukin-1 Receptors; Intervention; Knowledge; Longevity; Mechanics; Methods; Microglia; Modeling; Molecular; Motor Activity; Mus; Neurologic; Neurons; Outcome; Outcome Assessment; Pathway interactions; Perfusion; Physiological; Prevention; Preventive measure; Process; RNA; Rehabilitation therapy; Reporting; Risk; Rodent; Role; Route; Structure; System; TNF gene; Thinking; Time; Tissue Model; Tissues; Transplantation; Trauma; Traumatic Brain Injury; United States; Weight; brain repair; brain tissue; cell type; controlled cortical impact; cost; healing; human tissue; improved; in vivo; in vivo Model; injured; injury and repair; insight; metabolomics; mouse model; novel; novel strategies; preclinical study; public health relevance; repaired; response; response to injury; three dimensional cell culture; transcriptome; transcriptomics

 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.

 描述（由申请人提供）：非常需要对创伤引起的脑损伤机制有新的见解。不同类型的头部外伤（从局灶性挫伤到脑震荡）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，以减轻儿童和成人面临的这一主要风险，并采取新的预防措施。为了满足这一重大且不断增长的需求，我们计划在体外利用新型 3D 类脑组织，结合动物研究，将损伤和反应的标记物和机制关联起来。我们的假设是，具有模仿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大脑功能和对机械损伤的反应提供生理相关的读数，从而研究涉及创伤性脑损伤和修复的机制。这种相关性将为损伤激活的通路、损伤类型如何影响不同通路、大脑如何响应这些不同通路而愈合提供新的重要见解，并帮助确定干预和治疗的新线索。受不同类型损伤（例如惯性和重量下降）影响的体外 3D 组织（啮齿动物和人类）与体内啮齿动物研究的结合，将为以前未追求的结果提供全面的评估，同时也提高转化相关性。维持结构和功能数月的组织模型的可用性允许对结果（遗传、生化、代谢组学、电生理学）进行急性和慢性评估。这些读数将为此类伤害的因果关系提供前所未有的洞察和解释。我们初步了解 涉及 Akt 和 mTOR 激活等机制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，应该为损伤效应和干预模式提供前所未有的新见解。所有计划都有大量初步数据的支持。