Age-related alterations to NADPH oxidase and glial cell activation after spinal cord injury

脊髓损伤后 NADPH 氧化酶和神经胶质细胞活化的年龄相关变化

• 批准号: 9051752
• 负责人: Ramona E. von Leden
• 金额: $ 2.71万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9051752
• 关键词: Acute; Adult; Affect; Age; Age-Months; Aging; Apoptotic; Astrocytes; Biochemical; Biochemistry; Brain; Cell Fractionation; Cell Survival; Cells; Chronic; Cicatrix; Cods; Contusions; Data; Detection; Diagnosis; Elderly; Enzymes; Evaluation; Family; Future; Gene Expression; Human; Immune; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Injury; Label; Lesion; Life; Macrophage Activation; Measures; Microglia; Modeling; Morphology; Motor; Mus; NADP; NADPH Oxidase; Neuraxis; Neuroglia; Neurons; Outcome; Oxidases; Oxidative Stress; Phenotype; Play; Population; Production; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Research Personnel; Rest; Rodent; Role; Severities; Site; Source; Spinal; Spinal Cord; Spinal cord injury; Stimulus; Techniques; Testing; Tissues; Trauma; Traumatic Brain Injury; Up-Regulation; Work; age effect; age related; aged; aging population; base; cell type; comorbidity; cytokine; disability; functional outcomes; improved; inhibitor/antagonist; insight; middle age; neurotoxic; public health relevance; repaired; research study; response; response to injury; stressor; therapeutic target; young adult

 DESCRIPTION (provided by applicant): Over 250,000 people in the US are currently living with disabilities related to spinal cord injury (SCI). The number of SCI's among the aging population has been steadily increasing since the 1980's, and is associated with high rates of co-morbidities. Oxidative stress and reactive oxygen species (ROS) are increased in aging tissue and have been causally implicated in tissue damage and chronic inflammation in the central nervous system (CNS). These stressors influence the activity of glial cells, contributing to the delayed recovery to SCI seen in the aging population. No work to date has examined age-related alterations in glial cell response to SCI. The NADPH oxidase (NOX) family of enzymes is suggested to play a modulatory role in microglial/macrophage activation, inflammation and tissue damage through the production of ROS, and is chronically up-regulated after SCI. NOX, microglia and astrocytes all show altered profiles with increased inflammatory morphology and basal activation states in both human and rodent aged populations. Thus, we hypothesize that age-related upregulation in NOX activity and expression leads to increased proinflammatory glial cell activation states, resulting in exaggerated glial responses and diminished recovery to spinal cord injury. To test this hypothesis, we propose three specific aims. In aim 1, we will characterize basal glial cell activation states and NOX expression and activity in the aging rodent spinal cord. In this aim, we will use double labeled immunohistochemistry and biochemical techniques to characterize NOX and glial cell activation state in 3 and 12 month aged rats. In aim 2, we will demonstrate the effects of aging on NOX expression and activity, glial cell activation, lesion size and functional recovery after spinal cod injury. In this aim, we will assess NOX and glial cell activation after a moderate contusion SCI in 3 and 12 month aged rats using immunohistochemistry, biochemistry, RT-qPCR and functional assessment. In aim 3, we will evaluate the effect of inhibition of NOX activity and expression on basal glial activation and response to injury. In this aim, we will assess the modulatory effects o NOX on microglia and astrocyte activation in aged rats using a NOX2 specific inhibitor. This effect will be investigated using immunohistochemistry, biochemistry, subcellular fractionation and functional assessment. The data generated in these aims will help to guide researchers and clinicians in more effective diagnosis and may provide important insight into potential future therapeutic targets for SCI in the aging population.

 描述（由适用提供）：美国目前有25万人患有与脊髓损伤有关的疾病（SCI）。自1980年代以来，老龄化人口中的SCI数量一直在稳步增加，并且与合并症的率高有关。在衰老组织中，氧化应激和活性氧（ROS）增加，并且意外与中枢神经系统（CNS）的组织损伤和慢性炎症有关。这些压力源会影响神经胶质细胞的活性，这导致延迟恢复到老龄化的人群中的SCI。迄今为止，尚无研究检查与SCI的神经胶质细胞反应中与年龄相关的变化。建议酶的NADPH氧化酶（NOX）家族通过ROS的产生在小胶质细胞/巨噬细胞激活，感染和组织损伤中起调节作用，并在长期上调。科学。 NOX，小胶质细胞和星形胶质细胞均显示出变化的特征，在人类和啮齿动物老年人群中，炎症形态和基本激活状态增加。因此，我们假设在NOX活性中与年龄相关的上调和表达导致促炎性神经胶质细胞激活态增加，从而导致神经胶质反应的夸张，并减少对脊髓损伤的恢复。为了检验这一假设，我们提出了三个具体目标。在AIM 1中，我们将在衰老的啮齿动物脊髓中表征基本的神经胶质细胞激活状态和NOX表达和活性。在此目标中，我们将使用双重标记的免疫组织化学和生化技术来表征3和12个月大鼠的NOX和神经胶质细胞激活状态。在AIM 2中，我们将展示衰老对NOX表达和活性，神经胶质细胞激活，病变大小和脊柱COD损伤后功能恢复的影响。这个目的，我们将评估现代挫伤SCI之后的NOX和神经胶质细胞激活 使用免疫组织化学，生物化学，RT-QPCR和功能评估的3个月和12个月大鼠。在AIM 3中，我们将评估NOX活性和表达对基本神经胶质激活和对损伤的反应的影响。在此目标中，我们将使用NOX2特异性抑制剂评估老年大鼠小胶质细胞和星形胶质细胞激活的调节作用。将使用免疫组织化学，生物化学，亚细胞分级和功能评估来研究这种效果。这些目标中产生的数据将有助于指导研究人员和临床医生进行更有效的诊断，并可能对衰老人群中SCI的潜在未来治疗靶标的重要见解。