Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma.

重新编程小胶质细胞表观遗传途径以促进脑外伤后的认知恢复。

• 批准号: 10381618
• 负责人: ALAN Ira FADEN
• 金额: $ 45.1万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381618
• 关键词: Address; Affective; Aging; Alzheimer' s Disease; Anti-Inflammatory Agents; Automobile Driving; Brain; Brain Injuries; CSF1R gene; Cells; Chronic; Chronic Brain Injury; Cognitive; Cognitive deficits; Data; Dementia; Disease; Environment; Epigenetic Process; Excision; Flow Cytometry; Functional disorder; Genes; Goals; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Immunologic Memory; Immunologics; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Lead; Long-Term Effects; Mediating; Methylation; Microglia; Modification; Molecular; Molecular Profiling; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Deficit; Pathologic; Pathway interactions; Phagocytes; Phagocytosis; Pharmacology; Phenotype; Population; Process; Promoter Regions; Recovery of Function; Role; Testing; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Traumatic Brain Injury recovery; Up-Regulation; attenuation; chronic traumatic encephalopathy; cognitive function; cognitive recovery; cytokine; epigenetic regulation; gene therapy; histone methylation; improved; inflammatory milieu; inhibitor; nano-string; neurobehavioral; neuroinflammation; neurological recovery; neuropsychiatry; neurorestoration; neurotoxic; novel; progressive neurodegeneration; response; senescence

Project Summary: Traumatic brain injury (TBI) triggers delayed molecular secondary injury cascades, including chronic neuroinflammation, that contribute to progressive tissue loss and neurological deficits, including dementia. We have shown that microglia are chronically activated for months-to-years following experimental TBI in mice, contributing to progressive neurodegeneration associated with cognitive decline. Microglia also undergo changes in their activation profile that may contribute to cognitive decline during neurodegenerative diseases, including Alzheimer’s disease (AD) and dementias of non-AD type. An important component of these pathological states is the maladaptive transformation of microglia from a neurorestorative/neuroprotective phenotype to a persistent, dysfunctional neurotoxic activation state. Our new studies show that microglia isolated from chronically injured brain display deficits in phagocytosis in parallel with elevations of pro-inflammatory cytokines and senescence markers, indicative of a chronic dysfunctional/neurotoxic activation state. Furthermore, we identify specific histone acetylation (H3K9ac) and methylation (H3K27me3) changes in neurotoxic microglia, which implicate intrinsic epigenetic mechanisms as drivers of this chronic phenotype. Importantly, new pilot data show that global removal of microglia from the chronically injured brain by short-term administration of a CSF1R inhibitor (PLX5622) starting at 1-month post-injury results in the repopulation of the injured brain with microglia with an anti-inflammatory phenotype. This process of resetting microglial activation after TBI dampens the chronic neuroinflammatory environment and improves long-term motor and cognitive function recovery. Thus, our data indicates that erasing posttraumatic immunological memory, by removing microglia epigenetically programmed toward a neurotoxic activation state, promotes neuroprotective microglial activation responses and improves long-term neurological recovery. Therefore, we hypothesize that moderate- severe TBI induces specific epigenetic mechanisms in microglia that promote a chronic neurotoxic activation state, causing progressive neurodegeneration and cognitive deficits. Moreover, we predict that strategies that eliminate this microglial phenotype and/or targeted inhibition of pro-inflammatory epigenetic mechanisms, even at highly delayed time points after TBI, can substantially improve long-term cognitive recovery. Here, we will use neurobehavioral, immunological, and molecular approaches to test our novel hypotheses as outlined in following specific aims: 1) To elucidate TBI-induced intrinsic epigenetic changes that lead to chronic microglial dysfunction, with a shift toward a pro-inflammatory, neurotoxic phenotype. 2) To demonstrate that microglia that repopulate the injured brain following delayed administration of CSF1R inhibitor are reprogramed toward a neurorestorative and neuroprotective phenotype that improves cognitive function. 3) To determine whether delayed interventions that target specific epigenetic mechanisms promote the neurorestorative/neuroprotective microglial phenotype and improve long-term functional recovery after TBI.

项目摘要：创伤性脑损伤（TBI）触发了延迟分子继发性损伤级联，包括 慢性神经炎症，导致进行性组织丧失和神经系统缺陷，包括 失智。我们已经表明，在实验之后，小胶质细胞长期激活数月 小鼠的TBI，导致与认知能力下降相关的进行性神经退行性。小胶质细胞也 在神经退行性过程中可能导致认知下降的激活曲线发生变化 疾病，包括阿尔茨海默氏病（AD）和非AD类型的痴呆症。这些重要组成部分 病理状态是小胶质细胞的不良适应性转化 表型持续，功能失调的神经毒性激活状态。我们的新研究表明，小胶质细胞分离 从长期受伤的大脑显示吞噬作用的定义与促炎的升高并行 细胞因子和感应标记，表明慢性功能失调/神经毒性激活状态。 此外，我们确定了特定的组蛋白乙酰化（H3K9AC）和甲基化（H3K27me3）的变化 神经毒性的小胶质细胞，这将内在的表观遗传机理视为该慢性表型的驱动因素。 重要的是，新的试点数据表明，全球从短期内从长期造成的大脑中清除小胶质细胞 在伤害后1个月开始的CSF1R抑制剂（PLX5622）导致重生 用抗炎表型的小胶质细胞受伤的大脑。重置小胶质激活的过程 在TBI衰减后，慢性神经炎症环境并改善了长期运动和认知 功能恢复。这就是我们的数据表明，通过删除来消除创伤后免疫记忆 在神经毒性激活状态的表观遗传学编程的小胶质细胞，促进神经保护小胶质细胞 激活反应并改善长期神经恢复。因此，我们假设该中等 严重的TBI在小胶质细胞中诱导特定的表观遗传机制，从而促进慢性神经毒性激活 状态，导致进行性神经退行性和认知缺陷。此外，我们预测了这些策略 消除这种小胶质表型和/或针对性抑制促炎的表观遗传机制，甚至 在TBI之后的高度延迟时间点，可以大大改善长期认知恢复。在这里，我们将使用 神经行为，免疫学和分子方法检验我们的新假设，如以下概述 具体目的：1）阐明TBI诱导的内在表观遗传变化，导致慢性小胶质细胞功能障碍， 转向促炎性的神经毒性表型。 2）证明了重生的小胶质细胞 延迟施用CSF1R抑制剂后，受伤的大脑被重新编程为神经抑制剂 以及改善认知功能的神经保护表型。 3）确定是否延迟干预措施 该靶向特定的表观遗传机制促进了神经受到的/神经保护小胶质细胞表型 并改善TBI后的长期功能恢复。