TRAUMA TO THE DEVELOPING BRAIN--RESPONSE AND TREATMENT

发育中大脑的创伤——应对和治疗

• 批准号: 6393891
• 负责人: Ann-Christine Duhaime
• 金额: $ 10.69万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393891
• 关键词: NMDA receptors; biological models; brain; brain injury; contusions; experimental brain lesion; immature animal; inhibitor /antagonist; magnetic resonance imaging; neurogenesis; neuroprotectants; neurotoxins; nuclear magnetic resonance spectroscopy; swine; trauma

DESCRIPTION: (Applicant's Abstract): Traumatic brain injury is the most common cause of death and acquired disability in childhood in the United States. It has long been recognized in the clinical realm that infants and young children exhibit brain injury syndromes which are unique to this age group and are associated with particularly high morbidity and mortality. Because the brain changes dramatically during early development with respect to its mechanical properties, regional metabolism, myelination, vascular supply, neurotransmitter activity, and gene expression, its response to trauma is likely to differ significantly from that seen in adults. Therapies based on the response of the mature brain to injury therefore may be ineffective or even counterproductive in the immature nervous system. The few studies of brain injury in immaturity to date have relied primarily on rodent models, which differ in major morphologic and developmental characteristics from humans. Because of the morphometric and developmental similarities between the piglet and human brain we have developed a focal contusion model which is scaled for use in piglets at ages corresponding to human infants, toddlers, and adolescents. Use of this model will allow for the determination of age-specific differences in the histologic and pathophysiologic response of the brain to this common form of pediatric brain injury, and we hypothesize that vulnerability will be greatest in the youngest ages. These differences also will be visible in vivo using magnetic resonance imaging and spectroscopy in piglets after sealed focal injury, using the latest techniques for characterizing injury response in children. Similar age- dependent vulnerability of the immature brain to damage after trauma will correlate with a) physiologic instability after injury. Finally, because of these interrelated developmental changes including susceptibility to excitotoxic insult, we hypothesize that the neuroprotective efficacy of NMDA receptor antagonists will vary significantly with age. This important information will be useful in the development and testing of head injury therapies appropriate for infants and children.

描述：（申请人的摘要）：创伤性脑损伤是 最常见的死亡原因和童年时期的残疾 美国。 在临床领域长期以来一直认识到 婴儿和幼儿表现出脑损伤综合征 这个年龄段独有的，特别高 发病率和死亡率。因为大脑在 关于其机械性能，区域性的早期发展 代谢，髓鞘，血管供应，神经递质活性和 基因表达，其对创伤的反应可能有所不同 从成年人中可以看出这一点。基于反应的疗法 因此，成熟的大脑受伤可能是无效的甚至 不成熟的神经系统适得其反。少数研究 迄今为止不成熟的脑损伤主要依赖于啮齿动物 模型，在主要形态和发展方面有所不同 人类的特征。 由于形态计量学和 仔猪和人脑之间的发展相似性我们 开发了一个局灶性挫伤模型，该模型被缩放为用于仔猪 与人类婴儿，幼儿和青少年相对应的年龄。 使用 该模型将允许确定特定年龄的差异 在大脑对此的组织学和病理生理反应中 小儿脑损伤的常见形式，我们假设 在最年轻的年龄中，脆弱性将是最大的。 这些差异 也将使用磁共振成像在体内可见 密封局灶性损伤后小猪的光谱法，使用最新 表征儿童伤害反应的技术。 年龄相似 - 不成熟大脑在创伤后损害的依赖性脆弱性 受伤后的生理不稳定性将与a）生理不稳定相关。 最后， 由于这些相互关联的发展变化，包括 对兴奋性毒性侮辱的敏感性，我们假设 NMDA受体拮抗剂的神经保护功效将有所不同 随着年龄的增长很大。 这些重要信息将在 头部损伤疗法的开发和测试适合 婴儿和儿童。