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: 9884830
• 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/9884830
• 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/antagonist; 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) 引发延迟的分子继发性损伤级联反应，包括 慢性神经炎症，导致进行性组织损失和神经功能缺损，包括 我们已经证明，小胶质细胞在实验后数月至数年内会被长期激活。 小鼠脑损伤也会导致与小胶质细胞认知能力下降相关的进行性神经变性。 其激活谱发生变化，可能导致神经退行性疾病期间认知能力下降 疾病，包括阿尔茨海默病 (AD) 和非 AD 类型的痴呆症，这是这些疾病的重要组成部分。 病理状态是小胶质细胞从神经恢复/神经保护状态发生的适应不良转变。 我们的新研究表明，小胶质细胞被分离到持久的、功能失调的神经毒性激活状态。 慢性损伤的大脑显示吞噬作用缺陷，同时促炎细胞增多 细胞因子和衰老标记物，慢性功能障碍/神经毒性激活状态的指标。 此外，我们还发现了特定组蛋白乙酰化 (H3K9ac) 和甲基化 (H3K27me3) 的变化 神经毒性小胶质细胞，这表明内在的表观遗传机制是这种慢性表型的驱动因素。 重要的是，新的试点数据表明，短期内可从慢性损伤的大脑中全面清除小胶质细胞。 从受伤后 1 个月开始施用 CSF1R 抑制剂 (PLX5622) 会导致 具有抗炎表型的小胶质细胞受损的大脑，这是重置小胶质细胞激活的过程。 TBI 抑制慢性神经炎症环境并改善长期运动和认知能力 因此，我们的数据表明，通过消除创伤后免疫记忆。 小胶质细胞表观遗传编程为神经毒性激活状态，促进神经保护性小胶质细胞 激活反应并改善长期神经恢复因此，我们追求的是适度的。 严重的创伤性脑损伤会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变和认知缺陷。此外，我们预测该策略会 消除这种小胶质细胞表型和/或有针对性地抑制促炎表观遗传机制，甚至 在TBI后高度延迟的时间点，可以显着改善长期认知恢复，在这里，我们将使用。 神经行为、免疫学和分子方法来测试我们的新假设，如下所述 具体目标：1) 阐明 TBI 诱导的导致慢性小胶质细胞功能障碍的内在表观遗传变化， 向促炎、神经毒性表型转变 2) 证明小胶质细胞重新增殖。 延迟施用 CSF1R 抑制剂后受损的大脑会被重新编程以实现神经恢复 和改善认知功能的神经保护表型 3) 确定是否延迟干预。 针对特定表观遗传机制促进神经恢复/神经保护小胶质细胞表型 并改善 TBI 后的长期功能恢复。