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: 7628357
• 负责人: LINDA J. NOBLE
• 金额: $ 29.66万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628357
• 关键词: 4 year old; Address; Adult; Antioxidants; Area; Attention; Attenuated; Biological Models; Blood Vessels; Brain; Brain Injuries; Cause of Death; Cell Adhesion Molecules; Cell Death; Cells; Chemotactic Factors; Child; Childhood Injury; Clinical Data; Cognitive; Cognitive deficits; Demyelinations; Dependence; Development; Effectiveness; Environment; Enzymes; Evaluation; Event; Evolution; Experimental Models; Flow Cytometry; Future; Glutathione; Glutathione Reductase; Hippocampus (Brain); Impaired cognition; Indomethacin; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Learning; Lesion; Leukocytes; Magnetic Resonance Imaging; Measures; Memory; Methods; Microglia; Modeling; Mus; Neonatal; Neuronal Injury; Neurons; Outcome; Oxidation-Reduction; Oxidative Stress; Pattern; Process; RNase protection assay; Recovery; Recovery of Function; Relative (related person); Research; Research Personnel; Structure; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; Traumatic Brain Injury; Vascular Cell Adhesion Molecule-1; Wound Healing; base; behavior measurement; buthionine; cell injury; chemokine; cognitive function; cognitive recovery; critical period; defined contribution; disability; functional outcomes; glutathione peroxidase; immunocytochemistry; improved; injured; injury and repair; macrophage; motor deficit; myelination; neuron loss; overexpression; oxidative damage; prevent; programs; rapid growth; relating to nervous system; tool; wound

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（由申请人提供）：创伤性脑损伤（TBI）是儿童残疾的主要原因，并与显著的认知缺陷相关。最近的研究表明，创伤性脑损伤损害认知功能的程度更大，在儿童小于4岁比在年龄较大的儿童。虽然已经有相当大的努力，旨在了解创伤性脑损伤的病理生物学在成人的大脑很少知道创伤性脑损伤的后果在儿童，特别是在发展的关键时期。我们推测，未成熟大脑创伤后的认知障碍部分是早期炎症引起的细胞死亡的结果。我们进一步假设，这种早期炎症反应在受伤的未成熟大脑中被夸大，因为抗氧化剂储备不足。为了验证这些假设，我们将确定炎症对TBI后早期组织损伤的贡献，并确定抗氧化剂谷胱甘肽过氧化物酶（GPx）的活性增加是否会减少炎症和细胞损伤，从而支持结构和功能恢复。 这些研究将依赖于新开发的未成熟小鼠TBI模型，以解决4个目标。具体目标1将检验浸润性白细胞和小胶质细胞/巨噬细胞导致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）联合使用，以评估炎症对损伤和恢复过程的贡献。具体目标2将检验以下假设：受损脑中GPx活性增加可减少氧化应激/损伤、白细胞募集和屏障破坏。将在过表达GPx的脑损伤转基因小鼠（Tg）中与野生型（Wt）同窝仔比较抗氧化储备、氧化还原状态和炎症。具体目标3将测试这一假设，即从GPx活性增加的丰富的抗氧化剂储备，通过调节血管粘附分子和趋化因子减弱早期炎症反应。我们将确定是否血管粘附分子和趋化因子，定义RNase保护试验，和白细胞浸润优先发生在氧化应激的区域，如果这些事件改变GPx Tg相比，野生型小鼠。具体目标4将检验这一假设，即丰富的抗氧化储备是TBI后结构和认知恢复的决定因素。解剖学和行为测量以及MRI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。