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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 创伤性脑损伤（TBI）是儿童和青少年最重要的死亡和残疾原因，但对于将小儿脑损伤与成年人区分开的基本机制相对较少。人们理解了对未成熟大脑的创伤性生物力学损伤可以表现为慢性认知和行为问题，而发育潜力的丧失。可塑性被定义为一种机制，大脑通过该机制修饰细胞结构和功能以应对环境变化。越来越多的证据表明，小儿TBI会导致可塑性受损和神经传递的改变。谷氨酸代表了中枢神经系统中主要的兴奋性神经递质，并且与TBI的急性病理生理学密切相关，但对于正常发育和神经可塑性至关重要。该应用建议研究未成熟大脑中对TBI的谷氨酸能反应，尤其是涉及N-甲基-D-天冬氨酸（NMDA）受体的谷氨酸能反应。该提议的核心假设是，NMDA受体的功能障碍是发育性TBI后看到的可塑性丧失的基础，并且可以使用良好的经验实验模型TBI的模型TB，可以用电生理学（特定的目标3）和认知（特定的目标4）来测量这种扰动（特定目的1和2），特定的目标4）和使用良好的实验模型。通过确定这种重要的神经递质系统变化的伤害后时间过程，可以识别NMDA受体处于神经反应受损的窗口。然后，正确识别此时期将指导该应用的最终目标（特定目的5），即利用增加NMDA受体神经传递的药理剂，以使发育中大脑的分子特征正常化并减轻行为和认知缺陷。该提案为严格测试特定年龄的治疗策略提供了一个独特的机会，该策略旨在对最容易受到TBI（TBI，儿童）的患者群体有益。