Trauma to Developing Brain-Injury and Repair Mechanisms

创伤对脑损伤和修复机制的发展

• 批准号: 6965768
• 负责人: LINDA J. NOBLE
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965768
• 关键词: brain injury; cell death; chemokine; cognition disorders; enzyme activity; flow cytometry; gene expression; genetically modified animals; glutathione peroxidase; immunocytochemistry; inflammation; laboratory mouse; magnetic resonance imaging; trauma

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading cause of disability in children and is associated with significant cognitive deficits. Recent studies indicate that TBI impairs cognitive function to a greater extent in children less than 4 years of age than in older children. Although there has been a considerable effort directed toward understanding the pathobiology of TBI in the adult brain little is known about the consequences of TBI in the child, particularly during the critical period of development. We hypothesize that cognitive impairment after traumatic injury to the immature brain is in part a consequence of cell death resulting from early inflammation. We further hypothesize that this early inflammatory response is exaggerated in the injured, immature brain because of inadequate antioxidant reserves. To test these hypotheses, we will define the contribution of inflammation to early tissue damage after TBI and will determine if increased activity of the antioxidant glutathione peroxidase (GPx) will reduce inflammation and cell injury thereby supporting structural and functional recovery. These studies will rely on a newly developed model of TBI in the immature mouse to address 4 aims. Specific Aim 1 will test the hypothesis that infiltrating leukocytes and microglia/macrophages contribute to cell injury and impair cognitive recovery. Inflammatory blockade and leukocyte depletion will be used in conjunction with flow cytometry, immunocytochemistry and magnetic resonance imaging (MRI) to assess the contribution of inflammation to injury and recovery processes. Specific Aim 2 will test the hypothesis that increased GPx activity in the injured brain reduces oxidative stress/injury, leukocyte recruitment, and barrier disruption. Antioxidant reserve, redox state, and inflammation will be compared in brain injured transgenic mice (Tg) that overexpress GPx with wildtype (Wt) littermates. Specific Aim 3 will test the hypothesis that enriched antioxidant reserves from increased GPx activity attenuates the early inflammatory response through modulation of vascular adhesion molecules and chemokines. We will determine if vascular adhesion molecules and chemokines, defined by Rnase protection assays, and leukocyte infiltration occur preferentially in regions of oxidative stress and if these events are altered in GPx Tg as compared to Wt mice. Specific Aim 4 will test the hypothesis that enriched antioxidant reserves are a determinant of structural and cognitive recovery after TBI. Anatomical and behavioral measures and MRI, will be used to determine if a sustained increase in GPx activity alters cell loss and demyelination, thereby improving cognitive outcome.

描述(申请人提供)：创伤性脑损伤(TBI)是导致儿童残疾的主要原因，并与严重的认知缺陷有关。最近的研究表明，与年龄较大的儿童相比，脑外伤对4岁以下儿童认知功能的损害更大。虽然已经有相当多的努力针对理解脑外伤在成人脑中的病理生物学，但对脑外伤对儿童的影响，特别是在发育的关键时期，人们知之甚少。我们假设，未成熟大脑的创伤性损伤后的认知障碍部分是早期炎症导致的细胞死亡的结果。我们进一步假设，由于抗氧化剂储备不足，这种早期的炎症反应在受伤的未成熟大脑中被夸大了。为了验证这些假说，我们将确定炎症对脑外伤后早期组织损伤的贡献，并将确定抗氧化剂谷胱甘肽过氧化物酶(GPX)活性的增加是否会减少炎症和细胞损伤，从而支持结构和功能的恢复。 这些研究将依赖于一种新开发的未成熟小鼠脑外伤模型来解决四个目标。具体目标1将检验渗透的白细胞和小胶质细胞/巨噬细胞有助于细胞损伤和损害认知恢复的假设。炎症阻断和白细胞清除将与流式细胞术、免疫细胞化学和磁共振成像(MRI)结合使用，以评估炎症对损伤和恢复过程的贡献。《特定目标2》将验证这一假说，即受损大脑中GPX活性的增加可以减少氧化应激/损伤、白细胞募集和屏障破坏。脑损伤转基因小鼠(TG)过表达GPX与野生型(Wt)小鼠的抗氧化储备、氧化还原状态和炎症反应将进行比较。具体目标3将验证这样一个假设，即通过调节血管黏附分子和趋化因子，通过增加GPX活性来丰富抗氧化剂储备，可以减弱早期的炎症反应。我们将确定由核糖核酸酶保护试验定义的血管黏附分子和趋化因子以及白细胞渗透是否优先发生在氧化应激区域，以及与Wt小鼠相比，这些事件是否发生了改变。具体目标4将检验这一假设，即丰富的抗氧化剂储备是脑外伤后结构和认知恢复的决定因素。解剖学和行为学测量以及核磁共振将用于确定GPX活性的持续增加是否会改变细胞丢失和脱髓鞘，从而改善认知结果。