TRAUMA TO THE DEVELOPING BRAIN--RESPONSE AND TREATMENT

描述：(申请人摘要)：创伤性脑损伤是 儿童时期最常见的死亡原因和后天残疾 美国。长期以来，临床领域已经认识到 婴幼儿表现出脑损伤综合征，这些症状是 这是这个年龄段独有的，与特别高的 发病率和死亡率。因为大脑在过程中发生了巨大的变化 关于其机械性能、地区性的早期开发 代谢、髓鞘形成、血管供应、神经递质活性和 基因表达，它对创伤的反应可能会有所不同 这与成年人的情况有显著差异。基于反应的治疗方法 因此，成熟大脑的损伤可能是无效的，甚至是无效的 在不成熟的神经系统中会适得其反。少数几个问题研究 到目前为止，未成熟的脑损伤主要依靠啮齿动物 模型，在主要形态和发育方面有所不同 人类的特征。因为形态测量学和 小猪和人类大脑的发育相似之处 开发了一种局灶性挫伤模型，该模型已缩放用于仔猪 与人类婴儿、学步儿童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 在组织学和大脑对此的病理生理反应中 儿童脑损伤的常见形式，我们假设 在最年轻的时候，脆弱性将是最大的。这些差异 也将在活体内使用磁共振成像和 使用最新的光谱分析技术对仔猪闭合性局灶伤后的光谱进行研究 描述儿童伤害反应的技术。年龄相仿- 未成熟脑对创伤后损伤的依赖性易损性 将与a)受伤后的生理不稳定性有关。最后， 由于这些相互关联的发展变化，包括 对兴奋毒性侮辱的敏感性，我们假设 NMDA受体拮抗剂的神经保护效果将有所不同 随着年龄的增长显著增加。这一重要信息将在 开发和测试适用于以下方面的头部损伤治疗方法 婴儿和儿童。

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.