RESTORATION OF PLASTICITY AFTER PEDIATRIC TRAUMATIC BRAIN INJURY

小儿脑外伤后可塑性的恢复

• 批准号: 8171118
• 负责人: CHRISTOPHER C GIZA
• 金额: $ 0.3万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171118
• 关键词: Acute; Adolescent; Adult; Age; Behavioral; Biomechanics; Brain; Cause of Death; Child; Childhood; Chronic; Cognitive; Cognitive deficits; Computer Retrieval of Information on Scientific Projects Database; Development; Environment; Experimental Models; Functional disorder; Funding; Glutamates; Grant; Injury; Institution; Measures; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neuraxis; Neuronal Plasticity; Neurotransmitters; Pediatric Brain Injury; Problem behavior; Research; Research Personnel; Resources; Source; Structure; System; Testing; Therapeutic; Time; Traumatic Brain Injury; United States National Institutes of Health; design; disability; neurotransmission; patient population; relating to nervous system; response; restoration

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Traumatic brain injury (TBI) is the single most important cause of death and disability in children and adolescents, yet relatively little is known about the underlying mechanisms that distinguish pediatric brain injury from that in adults. It is understood the traumatic biomechanical injury to the immature brain can manifest as chronic cognitive and behavioral problems with a loss of developmental potential. Plasticity is defined as a mechanism by which the brain modifies cellular and network structure and function to respond to changes in the environment. There is increasing evidence that pediatric TBI can result in impaired plasticity and alterations in neurotransmission. Glutamate represents the major excitatory neurotransmitter in the central nervous system and is intimately involved in the acute pathophysiology of TBI, but also is critical for normal development and for neural plasticity. This application proposes to investigate the glutamatergic response to TBI in the immature brain, in particular, that which involves the N-methyl-D-aspartate (NMDA) receptor. The central hypothesis of this proposal is that dysfunction at the NMDA receptor underlies the loss of plasticity seen following developmental TBI, and that this perturbation can be measured molecularly (Specific Aims 1 and 2), electrophysiologically (Specific Aim 3) and cognitively (Specific Aim 4), using a well-characterized experimental model of pediatric TBI. By determining the post-injury time course of changes in this important neurotransmitter system, it will be possible to identify the window of impaired neural responsiveness at the NMDA receptor. Proper identification of this time period will then direct the final aim (Specific Aim 5) of this application, which is to utilize pharmacological agents that augment NMDA receptor neurotransmission to normalize the molecular profile of the developing brain and to alleviate behavioral and cognitive deficits. This proposal provides a unique opportunity to rigorously test an age-specific therapeutic strategy that is designed to be beneficial for the patient population most vulnerable to TBI, children.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 创伤性脑损伤（TBI）是儿童和青少年死亡和残疾的最重要原因，但人们对区分儿童脑损伤和成人脑损伤的潜在机制知之甚少。据了解，未成熟大脑的创伤性生物力学损伤可能表现为慢性认知和行为问题，并丧失发育潜力。可塑性被定义为大脑修改细胞和网络结构和功能以响应环境变化的机制。越来越多的证据表明，儿童创伤性脑损伤会导致可塑性受损和神经传递改变。谷氨酸是中枢神经系统中主要的兴奋性神经递质，与 TBI 的急性病理生理学密切相关，而且对于正常发育和神经可塑性也至关重要。本申请旨在研究未成熟大脑中对 TBI 的谷氨酸能反应，特别是涉及 N-甲基-D-天冬氨酸 (NMDA) 受体的谷氨酸能反应。该提议的中心假设是，NMDA 受体的功能障碍是发育性 TBI 后可塑性丧失的基础，并且这种扰动可以通过分子（具体目标 1 和 2）、电生理学（具体目标 3）和认知（具体目标 3）来测量。 4），使用特征良好的儿科 TBI 实验模型。通过确定这一重要神经递质系统的损伤后变化过程，将有可能识别 NMDA 受体神经反应性受损的窗口。正确识别该时间段将指导该应用的最终目标（具体目标 5），即利用增强 NMDA 受体神经传递的药物来使发育中的大脑的分子特征正常化并减轻行为和认知缺陷。该提案提供了一个独特的机会来严格测试特定年龄的治疗策略，该策略旨在造福于最容易遭受 TBI 的患者群体，即儿童。