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，并且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，TBI在不到4岁的儿童中会损害认知功能。尽管已经为理解成人大脑中TBI的病理生物学而做出了相当大的努力，但对儿童的后果却鲜为人知，尤其是在关键时期。我们假设对未成熟大脑的创伤性损伤后的认知障碍部分是由于早期炎症引起的细胞死亡的结果。我们进一步假设，由于抗氧化剂储量不足，受伤的，未成熟的大脑中这种早期炎症反应被夸大了。为了检验这些假设，我们将定义TBI后炎症对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）的活性是否增加，将减少炎症和细胞损伤，从而支持结构和功能恢复。 这些研究将依靠未成熟小鼠中新开发的TBI模型来解决4个目标。具体目标1将检验以下假设：浸润的白细胞和小胶质细胞/巨噬细胞有助于细胞损伤并损害认知恢复。炎症阻滞和白细胞耗竭将与流式细胞仪，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。具体目标2将检验以下假设：受伤大脑中GPX活性增加可减少氧化应激/损伤，白细胞募集和障碍破坏。将比较脑损伤的转基因小鼠（TG）的抗氧化剂储备，氧化还原状态和炎症，该小鼠（TG）用野生型（WT）同窝仔过表达GPX。具体目标3将检验以下假设，即增加GPX活性的富含抗氧化剂储量可通过调节血管粘附分子和趋化因子的调节来减轻早期炎症反应。我们将确定由RNase保护分析定义的血管粘附分子和趋化因子和白细胞浸润是否优先发生在氧化应激区域中，以及与WT小鼠相比，GPX TG中这些事件是否改变。具体目标4将检验以下假设：富集的抗氧化剂储量是TBI后结构和认知恢复的决定因素。解剖学和行为措施和MRI将用于确定GPX活性的持续增加是否改变了细胞丧失和脱髓鞘，从而改善了认知结果。