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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

基本信息

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
项目类别：
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

项目摘要

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.