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.

项目摘要 背景：老年人特别容易受到创伤性脑损伤（TBI），并且许多 研究报告说，老年TBI患者的临床预后较差。随着老年人口的继续增长 在2030年在美国估计有7150万 增加，将对国家卫生保健系统产生重大影响。尽管有这些增加 挑战，对负责老年TBI患者结果较差的基本机制的研究是 有限的。小胶质细胞激活是有助于慢性的关键次要损伤机制 TBI后神经变性和神经功能的丧失。小胶质细胞具有多种激活表型， 包括经典激活/M1状态，可能导致损伤和进行性组织的加剧 破坏，以及一种激活/M2状态，可抑制炎症反应和 促进组织修复。小胶质细胞是否分化为有助于继发损伤或 促进维修的M2状态取决于病变微环境中的信号 炎症）以及系统因素；两者都可能受年龄的影响。 描述：拟议研究的目的是研究基本的分子机制 TBI后，有助于增加老年大脑的小胶质激活和相关的神经毒性。我们 假设增加了衰老期间NADPH氧化酶活性 年轻的抗炎M2状态，到老年人的促炎M1状态。向M1转变 状态将导致老年人的神经退行性增加和神经系统效果较差。这 假设基于我们最近发表的初步数据，表明老年小鼠过多 与年轻小鼠相比，M1小胶质细胞激活对TBI，并在敲除小鼠中进行研究 表明小胶质细胞向M1激活状态的极化取决于活性 临界分子开关，NADPH氧化酶。在这里，我们建议研究一种新的分子干预 （NADPH氧化酶抑制）同时下调M1状态并上调M2状态，我们 将确定其促进年轻和老化的TBI大脑功能恢复和修复的潜力。具体的 目的包括：1）确定衰老是否改变了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）评估抑制NADPH氧化酶是否会减弱老年TBI小鼠的较差结果。 影响：了解将小胶质细胞向M2状态偏振的分子机制将至关重要 释放小胶质细胞在TBI后慢性恢复期间促进修复的内源性潜力。 鉴于衰老对TBI后神经炎症的影响，靶向NADPH氧化酶可能特别是 由于TBI，每年参加急诊室的142,000名老年人有益。