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: 7446689
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446689
• 关键词: Address; Adult; Age-Years; 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; Disruption; 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; Protein Overexpression; 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 developmental period; defined contribution; disability; functional outcomes; glutathione peroxidase; immunocytochemistry; improved; injured; injury and repair; macrophage; motor deficit; myelination; neuron loss; 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，并与严重的认知缺陷有关。最近的研究表明，创伤性脑损伤对4岁以下儿童的认知功能的损害比大一点的儿童更大。尽管在了解成人脑外伤的病理生物学方面已经做出了相当大的努力，但对儿童脑外伤的后果知之甚少，特别是在发育的关键时期。我们假设未成熟大脑外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，这种早期炎症反应在受伤的未成熟的大脑中被夸大了。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）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。