TRAUMA TO THE DEVELOPING BRAIN--RESPONSE AND TREATMENT

描述：（申请人的摘要）：创伤性脑损伤是指 在美国，儿童死亡和后天残疾最常见的原因 美国的 在临床领域中，长期以来一直认识到， 婴儿和幼儿表现出脑损伤综合征， 这是这个年龄组所特有的， 发病率和死亡率。因为大脑会发生巨大的变化 机械性能方面的早期发展，区域 代谢，髓鞘形成，血管供应，神经递质活性，和 基因表达，其对创伤的反应可能不同， 与成年人相比有显著差异。基于反应的治疗 因此，成熟大脑的损伤可能是无效的，甚至 在未成熟的神经系统中起反作用少数研究 迄今为止，未成年人的脑损伤主要依赖于啮齿动物 模型，其在主要形态和发育方面不同 人类的特征。 由于形态学和 我们发现的小猪和人类大脑的发育相似性 开发了一个局部挫伤模型，该模型按比例用于仔猪， 年龄相当于人类婴儿、幼儿和青少年。 使用 该模型将允许确定特定年龄的差异， 大脑对此的组织学和病理生理学反应 常见的小儿脑损伤，我们假设， 在最年轻的年龄段，脆弱性将最大。 这些差异 也将在体内使用磁共振成像可见， 光谱学在仔猪密封局灶性损伤后，使用最新的 描述儿童损伤反应的技术。 年龄相仿- 创伤后未成熟大脑对损伤的依赖性脆弱性 将与a）损伤后的生理不稳定性相关。 最后， 由于这些相互关联的发展变化， 易受兴奋性毒性损伤，我们假设， NMDA受体拮抗剂的神经保护功效将变化 随着年龄的显著。 这一重要信息将有助于 开发和测试适合于以下情况的头部损伤疗法 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.