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，导致进行性组织缺损和神经功能缺陷，包括 痴呆我们已经证明，小胶质细胞在实验性的神经刺激后会被慢性激活数月至数年。 小鼠TBI，导致与认知下降相关的进行性神经变性。小胶质细胞也 在神经退行性疾病期间，它们的激活特征发生变化，可能导致认知能力下降。 疾病，包括阿尔茨海默病（AD）和非AD型痴呆。其中的一个重要组成部分 病理状态是小胶质细胞从神经修复/神经保护的适应不良转化。 表型转化为持续的功能失调的神经毒性激活状态。我们的新研究表明， 从慢性损伤的大脑显示吞噬功能的缺陷与促炎性细胞因子的升高平行， 细胞因子和衰老标志物，指示慢性功能障碍/神经毒性活化状态。 此外，我们还鉴定了在细胞中特异性组蛋白乙酰化（H3 K9 ac）和甲基化（H3 K27 me 3）的变化。 神经毒性小胶质细胞，这涉及内在的表观遗传机制作为这种慢性表型的驱动因素。 重要的是，新的试点数据表明，短期内从慢性损伤的大脑中全面去除小胶质细胞 在损伤后1个月开始施用CSF 1 R抑制剂（PLX 5622）导致在损伤后1个月开始施用CSF 1 R抑制剂（PLX 5622）导致在损伤后1个月开始施用CSF 1 R抑制剂（PLX 5622）导致在损伤后1个月开始施用CSF 1 R抑制剂。 具有抗炎表型的小胶质细胞的受损脑。这个重置小胶质细胞激活的过程 TBI后抑制慢性神经炎症环境，改善长期运动和认知能力 功能恢复因此，我们的数据表明，消除创伤后免疫记忆， 小胶质细胞在表观遗传学上被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，我们假设- 严重TBI诱导小胶质细胞中促进慢性神经毒性激活的特定表观遗传机制 状态，导致进行性神经变性和认知缺陷。此外，我们预测， 消除这种小胶质细胞表型和/或靶向抑制促炎表观遗传机制，甚至 在TBI后高度延迟的时间点，可以显著改善长期认知恢复。在这里，我们将使用 神经行为学、免疫学和分子学方法来测试我们的新假设，如下所述 具体目的：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， 向促炎性神经毒性表型转变。2)为了证明小神经胶质细胞的再生 在延迟施用CSF 1 R抑制剂后，受损的大脑被重新编程为神经恢复性的， 和改善认知功能的神经保护表型。3)为了确定延迟干预是否 靶向特定的表观遗传机制促进神经修复/神经保护性小胶质细胞表型 并改善TBI后的长期功能恢复。