Trauma to Developing Brain-Oxidative Events and Recovery

描述(申请人提供)：创伤性脑损伤是首位 儿童残疾的原因，通常与显著的 认知和运动障碍。最近的研究表明，创伤性脑 损伤对儿童的运动和认知功能的损害程度更大 小于4岁的儿童比年龄较大的儿童。对此有一种解释 脆弱性的增加可能与受伤的时间有关，这 发生在发展的关键时期，以快速增长为特征 神经结构。尽管已经做出了相当大的努力 成人创伤性脑损伤的病理生物学认识 成人大脑，对创伤性脑损伤的后果知之甚少 在儿童中，特别是在发育的关键时期。我们 假设创伤性脑损伤在危重期 发育会导致脑内特定区域的神经元损伤和死亡 大脑，导致持续的功能缺陷。我们进一步假设 由于H202的产生和清除不足而导致的氧化应激 系统，是神经元损伤和行为缺陷的重要决定因素 在未成熟、受创伤的大脑中。提出了三个目标。第一个目标是 我们将建立幼鼠急性皮质挫伤模型。 (出生后第21天)小鼠。神经细胞丢失和神经胶质细胞反应性， 在光学显微镜水平上的定量定义，将在 最长6个月的认知和运动功能评估 受伤后。在第二个目标中，我们将测量氧化指标 应激/损伤在该模型中的作用，包括脂质过氧化和谷胱甘肽 水平、H202产量和抗氧化剂。在第三个目标中，我们将确定 如果减少氧化应激可以限制神经元损伤并促进认知 和运动恢复。局部神经元易损性与运动和认知 赤字将被评估。转基因将减轻氧化应激 谷胱甘肽过氧化物酶的过表达或自旋陷阱处理 抗氧化剂PBN。这些研究反映了琳达·诺布尔博士 在实验性创伤性脑损伤方面有专长的唐娜·费列罗博士， 一位新生儿缺氧缺血氧化损伤机制的专家，以及 雅各布·拉伯博士，他制定了定义良好的、敏感的 小鼠的认知和运动功能。这一综合的专业知识提供了 集中精力更好地了解未成熟大脑对 创伤性损伤，并开发最理想的治疗方法。

DESCRIPTION (provided by applicant): Traumatic brain injury is the leading cause of disability in children and is often associated with significant cognitive and motor deficits. Recent studies indicate that traumatic brain injury impairs motor and cognitive function to a greater extent in children less that 4 years of age than in older children. One explanation for this increased vulnerability may be related to the timing of the injury, which occurs during the critical period of development, characterized by rapid growth of neural structures. Although there has been a considerable effort directed toward understanding the pathobiology of traumatic brain injury in the mature adult brain, little is known about the consequences of traumatic brain injury in the child, particularly during the critical period of development. We hypothesize that traumatic brain injury during the critical period of development causes neuronal injury and death within specific regions of the brain, resulting in persistent functional deficits. We further hypothesize that oxidative stress, resulting from production of H202 and inadequate scavenging systems, are important determinants of neuronal injury and behavioral deficits in the immature, traumatized brain. Three aims are proposed. In the first aim we will develop a model of acute cortical contusion injury in the immature (postnatal day 21) mouse. Neuronal cell loss and glial reactivity, quantitatively defined at the light microscopic level, will be evaluated in concert with assessments of cognitive and motor function up to 6 months post-injury. In the second aim, we will measure indicators of oxidative stress/injury in this model, including lipid peroxidation and glutathione levels, H202 production, and antioxidants. In the third aim we will determine if reducing oxidative stress will limit neuronal injury and promote cognitive and motor recovery. Regional neuronal vulnerability and motor and cognitive deficits will be evaluated. Oxidative stress will be reduced by transgenic overexpression of glutathione peroxidase or by treatment with the spin-trap antioxidant PBN. These studies reflect a collaboration between Dr. Linda Noble, who has expertise in experimental traumatic brain injury, Dr. Donna Ferriero , an expert on mechanisms of oxidative injury in neonatal hypoxia-ischemia, and Dr. Jacob Raber, who has developed well defined, sensitive measures of cognitive and motor function in the mouse. This combined expertise offers a focused effort to better understand the vulnerability of the immature brain to traumatic injury and to develop the most optimal therapeutic approaches.