Trauma to Developing Brain-Oxidative Events and Recovery

描述（由申请人提供）：创伤性脑损伤是主要的 儿童残疾的原因，往往与重大 认知和运动缺陷。最近的研究表明， 伤害在更大程度上损害儿童的运动和认知功能 小于4岁的儿童比年龄较大的儿童。对此的一种解释 脆弱性的增加可能与受伤的时间有关， 发生在发展的关键时期，以快速增长为特征 的神经结构。尽管已经有相当大的努力 了解成熟期脑外伤的病理生物学 成年人的大脑，对创伤性脑损伤的后果知之甚少 尤其是在儿童发展的关键时期。我们 创伤性脑损伤关键期假说 发育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， 氧化应激，由H2 O2的产生和清除不足引起 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。在第一个目标中 我们将建立一个未成熟大鼠大脑皮质急性挫伤模型， （出生后第21天）小鼠。神经元细胞损失和神经胶质反应， 在光学显微镜水平定量定义，将在 与长达6个月的认知和运动功能评估一致 受伤后。在第二个目标中，我们将测量氧化的指标， 该模型中的应激/损伤，包括脂质过氧化和谷胱甘肽 水平、H2 O2产生和抗氧化剂。在第三个目标中，我们将确定 如果减少氧化应激将限制神经元损伤并促进认知 和运动恢复区域神经元脆弱性与运动和认知 赤字将得到评估。通过转基因将减少氧化应激 谷胱甘肽过氧化物酶的过度表达或用自旋捕集器处理 抗氧剂PBN。这些研究反映了琳达诺布尔博士， 她在实验性创伤性脑损伤方面很有经验，唐娜·费列罗博士， 新生儿缺氧缺血性氧化损伤机制专家， Jacob Raber博士，他已经开发出定义明确，敏感的测量方法， 小鼠的认知和运动功能。这种综合的专业知识提供了一个 专注于更好地了解未成熟大脑的脆弱性， 创伤性损伤，并开发最佳的治疗方法。

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.