Novel role and mechanisms of histone deacetylases in traumatic brain injury

组蛋白脱乙酰酶在创伤性脑损伤中的新作用和机制

• 批准号: 10255988
• 负责人: MICHAEL V L BENNETT
• 金额: $ 47.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255988
• 关键词: Ablation; Bone Marrow; Brain; Brain Injuries; Cerebrum; Clinical; Cognitive; Development; Dose; Emotional; Encephalitis; Excision; Female; Functional disorder; Gender; Genetic; Genetic Transcription; HDAC1 gene; HDAC2 gene; HDAC3 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Lysine; Macrophage Activation; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Mus; Nervous System Physiology; Neuronal Injury; Neurons; Outcome; Pharmacology; Phenotype; Pilot Projects; Play; Post-Translational Protein Processing; Proteins; Quality of life; Recovery; Recovery of Function; Rehabilitation therapy; Resolution; Role; STAT1 protein; Sensorimotor functions; Signal Pathway; Signal Transduction; Stretching; Structure; Tamoxifen; Testing; Therapeutic; Time; Tissues; Traumatic Brain Injury; aged; brain remodeling; brain repair; brain tissue; cognitive function; conditional knockout; controlled cortical impact; functional group; gray matter; improved; in vitro Model; in vivo; inhibitor/antagonist; injury and repair; macrophage; male; member; neurobehavioral; neuroinflammation; neuroprotection; neuropsychiatry; neurorestoration; neurotoxicity; new therapeutic target; non-histone protein; novel; novel therapeutic intervention; preservation; prevent; response; sex; subcutaneous; therapeutic evaluation; therapeutic target; tool; white matter; young adult

Emerging evidence implicates a pivotal role of cerebral inflammation in the pathophysiology of traumatic brain injury (TBI). Following TBI, microglia/macrophages may assume distinct pro-inflammatory or inflammation- resolving phenotypes, which potentiate brain injury or facilitate brain repair, respectively. The intracellular molecular switches that determine microglial/macrophage functional phenotypes after TBI are poorly understood. Identifying such molecular mechanisms may reveal novel targets to tune microglia/macrophages toward the reparative inflammation-resolving phenotype and improve long-term TBI outcomes. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histone and non-histone proteins, thereby regulating not only gene transcription but also the activity of various proteins through post-translational modifications. Previous studies by us and others demonstrate that pan-inhibitors of Class I HDACs (HDAC1, 2, 3, 8) mitigate brain inflammation and improve neurological functions after TBI. However, it is imperative to elucidate the role of different HDAC subtypes, in order to focus on specific therapeutic targets without disrupting the beneficial functions of some HDACs in post-injury brain repair. To date, the HDAC subtype responsible for protection against TBI is unknown. It is also not known if the cellular/molecular mechanisms underlying HDAC inhibitor-afforded protection involve the alteration of microglial/macrophage phenotype. Our pilot studies show for the first time that: 1) Microglia/macrophage-specific knockout (mKO) of HDAC3, but not HDAC1 or HDAC2, improves neurobehavioral outcomes after TBI. 2) HDAC3 mKO improves gray and white matter integrity, and mitigates neuroinflammation after TBI. 4) HDAC3 inhibition ameliorates pro- inflammatory microglia-mediated neurotoxicity after neuronal stretch injury (NSI), an in vitro TBI model. 5) HDAC3 inhibition reduces the activation of signal transducer and activator of transcription 1 (STAT1), a key molecule that mediates pro-inflammatory responses in microglia/macrophages. 6) Subcutaneous delivery of RGFP966, a brain-penetrant, potent, and specific HDAC3 inhibitor, ameliorates inflammation and sensorimotor deficits after TBI. Given these observations, we propose three specific aims to test the novel hypothesis that genetic or pharmacological ablation of HDAC3 provides neuroprotection and improves brain repair and long-term outcomes after TBI by promoting inflammation-resolving microglial/macrophage responses. Aim 1: Test if HDAC3 mKO improves gray and white matter integrity and long-term neurological functions after TBI. Controlled cortical impact (CCI) will be induced in mice of both sexes with tamoxifen-inducible HDAC3 knockout in microglia/macrophages. Aim 2: Test if genetic knockout of the HDAC3-STAT1 signaling pathway shifts microglia/macrophages toward the beneficial and inflammation-resolving phenotype after TBI. Aim 3: Test the therapeutic potential of the specific HDAC3 inhibitor RGFP966 in resolution of inflammation and improvement of long-term TBI outcomes in young adult and aged mice of both genders.

新兴证据暗示脑炎在创伤性大脑的病理生理学中的关键作用 受伤（TBI）。在TBI之后，小胶质细胞/巨噬细胞可能会假定促炎或炎症 - 解决表型，分别增加脑损伤或促进脑修复。细胞内 确定TBI后小胶质细胞/巨噬细胞功能表型的分子开关 理解。识别这种分子机制可能会揭示出针对小胶质细胞/巨噬细胞的新目标 迈向修复炎症的表型并改善长期TBI结局。 组蛋白脱乙酰基酶（HDACS）催化从组蛋白和非固定蛋白中去除乙酰基， 从而不仅调节基因转录，还调节各种蛋白质的活性通过翻译后的活性 修改。我们和其他人的先前研究表明，I类HDAC的泛抑制剂（HDAC1，2， 3，8）减轻脑部炎症并改善TBI后神经功能。但是，必须 阐明不同HDAC亚型的作用，以专注于没有特定的治疗靶标 破坏一些HDAC在伤害后脑修复中的有益功能。迄今为止，HDAC子类型 负责防止TBI的保护是未知的。还不知道细胞/分子机制是否 基本的HDAC抑制剂耐用保护涉及小胶质细胞/巨噬细胞表型的改变。 我们的试点研究首次表明：1）HDAC3的小胶质细胞/巨噬细胞特异性敲除（MKO），但 不是HDAC1或HDAC2，可改善TBI后神经行为结果。 2）HDAC3 MKO改善了灰色和 白质完整性，并减轻TBI后神经炎症。 4）HDAC3抑制可改善促值 神经元拉伸损伤（NSI）（一种体外TBI模型）后炎性小胶质细胞介导的神经毒性。 5） HDAC3抑制减少了转录1（STAT1）的信号换能器和激活因子的激活（键） 介导小胶质细胞/巨噬细胞中促炎反应的分子。 6）皮下交付 RGFP966，一种脑渗透剂，有效和特定的HDAC3抑制剂，可以改善炎症和感觉运动 TBI之后的缺陷。鉴于这些观察结果，我们提出了三个特定的目的，以检验新的假设，即 HDAC3的遗传或药理消融提供神经保护并改善脑修复和 TBI后长期结局通过促进炎症的小胶质细胞/巨噬细胞反应。 AIM 1：测试HDAC3 MKO是否改善了灰质和白质的完整性和长期神经功能之后 TBI。在两性男性的小鼠中，可控皮质撞击（CCI）将诱导他莫昔芬诱导的HDAC3 小胶质细胞/巨噬细胞中的敲除。 AIM 2：测试HDAC3-STAT1信号通路的遗传淘汰 将小胶质细胞/巨噬细胞转移到TBI后的有益和炎症的表型。目标3： 测试特定HDAC3抑制剂RGFP966的治疗潜力，以解决炎症和 两种性别的年轻人和老年小鼠的长期TBI结局改善。