Aging and Microglial Polarization

衰老和小胶质细胞极化

• 批准号: 9137860
• 负责人: PAULA C BICKFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137860
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Bioinformatics; Brain; Brain Injuries; Cell Aging; Cells; Chronic; Cognitive; Cognitive deficits; Complex; Craniocerebral Trauma; Data; Disease; Dominant-Negative Mutation; Elderly; Environment; Female; Gene Expression; Healthcare; Homeostasis; Immune Cell Activation; Impaired cognition; Inflammation; Inflammatory; Injury; Intervention; Lead; Learning; Link; Mass Spectrum Analysis; Microglia; Molecular; Morbidity - disease rate; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Nutraceutical; Organ; Organism; Outcome; Oxidative Stress; Parkinson Disease; Pathway interactions; Pharmacologic Substance; Phenotype; Predisposition; Process; Proteins; Proteomics; Regenerative response; Regulation; Reporting; Risk Factors; Signal Transduction; Stroke; Synaptic plasticity; Testing; Therapeutic; Tissues; Up-Regulation; Veterans; age related; aged; aging brain; base; biological adaptation to stress; cognitive function; design; functional outcomes; improved; knock-down; male; middle age; mortality; neurogenesis; normal aging; nuclear factor-erythroid 2; public health relevance; resilience; response

 DESCRIPTION (provided by applicant): Aging is the primary risk factor for neurodegenerative diseases and is associated with increased morbidity and mortality from acute and chronic injuries that lead to cognitive decline. One factor thought to contribute to this loss of resilience is a background of inflammation, however the underlying molecular alterations that lead to inflammation and the therapeutic approaches to improve resiliency are not fully understood (Bennet et al., 1996; Niccoli and Partridge, 2012; Michaud et al., 2013; Moll et al., 2014). Aging is a complex process that involves cellular senescence, a gradual loss of tissue homeostasis and declines in organ function. Aging involves multiple mechanisms that lead to alterations in organism homeostasis. It is becoming clear that the "environment" of the aged brain or other organs has a profound effect on the function of the brain and the regenerative response of the brain to diseases such as Parkinson's disease, Alzheimer's disease and acute or chronic injuries such as stroke or head injuries. The major contributors to this aging "environment" are oxidative stress and inflammation. Microglia are one of the main cells in the brain that contribute to both oxidative stress and inflammation. Microglia are constantly sensing the environment and respond differently depending on the signals received. In the aged brain microglia have been reported to be in a primed state where they have an increased response to pro-inflammatory signals and a blunted response to anti-inflammatory signals (Lee et al., 2013; Norden et al., 2014). This priming leads to an "environment" that is not conducive to neural plasticity related to cognitive function. THE SOLUTION TO THE PROBLEM: The key to modulating microglia in the aged brain is in understanding the complex interactions of proteins involved in upstream regulation of microglial priming. If we identify key regulators this will help us to design new strategies and/or improve current strategies for interventions to improve neural plasticity and cognitive status of elderly Veterans and also improve response to current therapies for neurodegenerative diseases. We propose to examine in depth the proteomic phenotypic response to various M1 and M2 signals in young versus aged microglia. We have already identified 2 major pathways linked to microglial priming under basal conditions in the aged brain, mTORC2 and Nuclear factor erythroid 2- related factor 2 (Nrf2). We will selectively modulate these pathways in microglia to improve synaptic plasticity and cognitive function in the aged brain and the aged brain following injury.

 描述（由申请人提供）： 衰老是神经退行性疾病的主要风险因素，并与导致认知能力下降的急性和慢性损伤的发病率和死亡率增加有关。被认为导致这种弹性损失的一个因素是炎症的背景，然而导致炎症的潜在分子改变和改善弹性的治疗方法尚未完全理解（Bennet et al.，1996年; Niccoli和Parkland，2012年; Michaud等人，2013; Moll等人，2014年）。衰老是一个复杂的过程，涉及细胞衰老，组织稳态的逐渐丧失和器官功能的下降。衰老涉及多种机制，导致生物体内平衡的改变。越来越清楚的是，老年大脑或其他器官的“环境”对大脑的功能以及大脑对诸如帕金森病、阿尔茨海默病等疾病以及诸如中风或头部损伤等急性或慢性损伤的再生反应具有深远的影响。造成这种老化“环境”的主要因素是氧化应激和炎症。小胶质细胞是大脑中导致氧化应激和炎症的主要细胞之一。小胶质细胞不断地感知环境，并根据接收到的信号做出不同的反应。据报道，在老年大脑中，小胶质细胞处于启动状态，其中它们对促炎信号的反应增强，而对抗炎信号的反应减弱（Lee等人，2013; Norden等人，2014年）。这种启动导致了一种不利于与认知功能相关的神经可塑性的“环境”。问题的解决方案：调节老年脑中小胶质细胞的关键是理解参与小胶质细胞启动上游调控的蛋白质的复杂相互作用。如果我们确定了关键的调控因子，这将有助于我们设计新的干预策略和/或改善目前的干预策略，以改善老年退伍军人的神经可塑性和认知状态，并改善对目前神经退行性疾病治疗的反应。我们建议深入研究年轻与老年小胶质细胞中各种M1和M2信号的蛋白质组表型反应。我们已经确定了在老年脑中基础条件下与小胶质细胞引发相关的2个主要途径，mTORC 2和核因子红细胞2相关因子2（Nrf 2）。我们将选择性地调节小胶质细胞中的这些通路，以改善老年大脑和损伤后老年大脑的突触可塑性和认知功能。