Microglial activation phenotypes and mechanisms of repair in the aged TBI brain

老年 TBI 大脑中的小胶质细胞激活表型和修复机制

• 批准号: 8630905
• 负责人: David J. Loane
• 金额: $ 33.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-28 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630905
• 关键词: Accident and Emergency department; Accounting; Adopted; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Brain; Cessation of life; Chronic; Chronic Phase; Clinical; Data; Elderly; Equilibrium; Genetic; Goals; Grant; Healthcare Systems; Hospitalization; Immune response; Individual; Inflammatory; Inflammatory Response; Injury; Intervention; Knockout Mice; Lead; Lesion; Measures; Mediating; Microglia; Molecular; Mus; NADPH Oxidase; Nerve Degeneration; Nervous System Physiology; Neurological outcome; Outcome; Oxidation-Reduction; Oxidative Stress; Patients; Phenotype; Population; Process; Public Health; Publishing; Reactive Oxygen Species; Recovery; Recovery of Function; Reporting; Research; Secondary to; Signal Transduction; Survivors; Time; Tissues; Traumatic Brain Injury; Visit; Work; acetovanillone; activity marker; age related; aged; aging brain; base; cytokine; functional outcomes; improved; injured; neuroinflammation; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; patient population; public health relevance; repaired; response; tissue repair

Project Summary Background: Elderly individuals are particularly vulnerable to traumatic brain injury (TBI), and numerous studies report clinically worse outcomes in elderly TBI patients. As the aged population continues to grow towards an estimated 71.5 million in 2030 in the US, the burden of TBI in the elderly is expected to dramatically increase, and will have a major impact on the national health care system. Despite these increasing challenges, research on the underlying mechanisms responsible for worse outcomes in elderly TBI patients is limited. Microglial activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function after TBI. Microglia have multiple activation phenotypes, including a classically activated/M1 state that may to lead to exacerbation of injury and progressive tissue destruction, and an alternatively activated/M2 state that serves to dampen the inflammatory response and promote tissue repair. Whether microglia differentiate into an M1 state that contributes to secondary injury or into an M2 state that promotes repair depends on the signals within the lesion microenvironment (pro- vs. anti- inflammatory), as well as systemic factors; both of which may be influenced by age. Description: The goal of the proposed research is to investigate the underlying molecular mechanisms that contribute to increased microglial activation and associated neurotoxicity in the aged brain following TBI. We hypothesis that increased NADPH oxidase activity during aging tips the M1/M2 microglia balance from favoring an anti-inflammatory M2 state in young, to a pro-inflammatory M1 state in elderly. This shift towards an M1 state will result in increased neurodegeneration and worse neurological outcomes in the elderly. This hypothesis is based on our recently published and preliminary data showing that aged mice have excessive M1 microglial activation in response to TBI compared to young mice, and studies in a knockout mouse which revealed that the polarization of microglia toward an M1 activation state following TBI depends on the activity of a critical molecular switch, NADPH oxidase. Here, we propose to investigate a novel molecular intervention (NADPH oxidase inhibition) to concurrently down-regulate the M1 state and up-regulate the M2 state, and we will determine its potential to promote functional recovery and repair in the young and aged TBI brain. Specific aims include: 1) Determine if aging alters NADPH oxidase activity and M1/M2-polarization of microglia after TBI, 2) Determine whether NADPH oxidase is a key molecular switch for M1 polarization of microglia after TBI, and 3) Assess whether inhibition of NADPH oxidase will attenuate poorer outcomes in aged TBI mice. Impact: Understanding the molecular mechanisms that polarize microglia towards an M2 state will be crucial to unlock the endogenous potential of microglia to promote repair during the chronic phase of recovery after TBI. Given the impact aging has on neuroinflammation after TBI, targeting NADPH oxidase may be particularly beneficial for the estimated 142,000 elderly individuals that attend the ER each year because of TBI.

项目概要 背景：老年人特别容易遭受创伤性脑损伤（TBI），并且许多人 研究报告老年 TBI 患者的临床结果较差。随着老龄化人口持续增长 到 2030 年，美国老年人 TBI 负担预计将大幅增加，预计将达到 7150 万 的增加，将对国家医疗保健体系产生重大影响。尽管这些增加 挑战，对老年 TBI 患者预后较差的潜在机制的研究正在进行 有限的。小胶质细胞激活是导致慢性损伤的关键继发性损伤机制 TBI 后神经退行性变和神经功能丧失。小胶质细胞具有多种激活表型， 包括经典激活/M1 状态，可能导致损伤加剧和组织进展 破坏，以及替代激活/M2状态，用于抑制炎症反应和 促进组织修复。小胶质细胞是否分化成导致继发性损伤的 M1 状态 进入促进修复的 M2 状态取决于病变微环境内的信号（亲与抗） 炎症）以及全身因素；两者都可能受到年龄的影响。 描述：拟议研究的目标是调查潜在的分子机制 有助于增加 TBI 后老年大脑中小胶质细胞的激活和相关的神经毒性。我们 衰老过程中 NADPH 氧化酶活性增加的假设提示 M1/M2 小胶质细胞平衡不利于 年轻时处于抗炎 M2 状态，老年人处于促炎 M1 状态。这次向 M1 的转变 这种状态将导致老年人的神经退行性病变加剧和神经系统结果恶化。这 假设是基于我们最近发表的初步数据，这些数据表明老年小鼠体内有过多的 与年轻小鼠相比，M1 小胶质细胞激活对 TBI 的反应，以及在基因敲除小鼠中的研究 研究表明，TBI 后小胶质细胞向 M1 激活状态的极化取决于活性 关键的分子开关 NADPH 氧化酶。在这里，我们建议研究一种新颖的分子干预 （NADPH氧化酶抑制）同时下调M1状态和上调M2状态，我们 将确定其促进年轻和老年 TBI 大脑功能恢复和修复的潜力。具体的 目标包括： 1) 确定衰老是否会改变 NADPH 氧化酶活性和小胶质细胞的 M1/M2 极化 TBI，2)确定NADPH氧化酶是否是TBI后小胶质细胞M1极化的关键分子开关， 3) 评估 NADPH 氧化酶的抑制是否会减轻老年 TBI 小鼠的较差结果。 影响：了解将小胶质细胞极化为 M2 状态的分子机制对于 释放小胶质细胞的内源性潜力，促进 TBI 后慢性恢复阶段的修复。 鉴于衰老对 TBI 后神经炎症的影响，针对 NADPH 氧化酶可能特别重要 每年约有 142,000 名因 TBI 前往急诊室的老年人受益。