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（由适用提供）：对因创伤引起的脑损伤机制有很大的新见解。从局灶性挫伤到咨询的不同类型的头部创伤造成的损害需要有关方法和结果的新思考，以提供治疗的窗口，以减轻对儿童和成人的重大风险，以及新的预防措施。为了满足这一主要需求，我们计划在体外利用新型的3D脑样组织，再加上动物研究，以将损伤和反应的标记和机制相关联。我们的假设是，模仿体内条件的结构和功能特征的3D小鼠和人类脑样组织将提供与物理相关的读数，以研究脑功能，以及对涉及创伤性脑损伤和修复的研究机制的机械损害的反应。这种相关性将为受伤激活的途径提供新的重要见解，损伤类型如何影响不同的途径，大脑如何响应这些不同的途径，并帮助识别新的潜在客户进行干预和治疗。体外3D组织（啮齿动物和人类）与体内啮齿动物研究的耦合，受到不同类型的损害（例如惯性和体重下降）的影响，将提供对先前未追求的结果的全面评估，同时也提高了翻译相关性。维持几个月结构和功能的组织模型的可用性允许对结局的急性和慢性评估（遗传，生化，代谢组学，电生理学）。这些读数将为这些类型的伤害提供前所未有的见识和解释因果关系。我们对 涉及AKT和MTOR激活等机制将为进一步研究提供合适的起点，而转录组学将允许鉴定新导线。最终，将体外模型和体内模型之间的转录组响应以及计划的其他读数进行比较，并在体外和体内进行急性和慢性临时响应，都应在急性和慢性临时响应中，对损害效应和干预模式进行前所未有的新见解。所有计划都得到广泛的初步数据的支持。