HDAC3 as a therapeutic target for intracerebral hemorrhage

HDAC3作为脑出血的治疗靶点

• 批准号: 10701321
• 负责人: Sangeetha Sukumari-Ramesh
• 金额: $ 39.08万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701321
• 关键词: Acetylation; Acute; Address; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Biological Assay; Brain; Brain Injuries; Brain hemorrhage; Brain region; Cell Line; Cerebral Edema; Cerebral hemisphere hemorrhage; Complex; DNA Binding; Data; Epigenetic Process; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Goals; Grant; HDAC1 gene; HDAC2 gene; HDAC3 gene; Hematoma; Hemin; Hemoglobin; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Hospitals; Inflammatory; Injury; Innate Immune System; Investigation; Macrophage; Macrophage Activation; Mass Spectrum Analysis; Mediating; Mediator; Microglia; Molecular; Mus; Myelogenous; Neurologic Deficit; Neurological outcome; Outcome; Patient-Focused Outcomes; Patients; Phagocytosis; Phenotype; Pre-Clinical Model; Prognosis; Protein Isoforms; Proteins; Proteomics; Public Health; Regulation; Regulator Genes; Reporting; Resolution; Role; Signal Transduction; Site; Sorting; Stimulus; Stroke; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Vorinostat; attenuation; clinically relevant; conditional knockout; disability; effective therapy; glial activation; improved; inhibitor; insight; knock-down; molecular targeted therapies; mortality; mouse model; neurobehavioral; neuroinflammation; neuroprotection; next generation; novel; pharmacologic; promoter; sex; targeted treatment; therapeutic target; transcription factor

Secondary brain injury is a leading cause of neurological deficits after intracerebral hemorrhage (ICH), a stroke subtype with no effective treatment. Despite the emerging role of epigenetic mechanisms in the complex pathophysiology of ICH, the isoform-specific role of histone deacetylases (HDACs) or the precise molecular mechanism of histone deacetylase inhibitor (HDACi)-mediated neuroprotection after ICH is yet to be defined. Based on our recent findings and compelling preliminary observations, our central hypothesis is that a class I HDAC isoform, HDAC3, is a critical molecular regulator of secondary brain injury and, thereby, neurological outcomes after ICH by modulating Nrf2 signaling. To test this hypothesis, three specific aims are proposed. Aim 1: To determine that pharmacological inhibition of HDAC3 attenuates secondary brain injury and improves hematoma resolution and neurobehavioral outcomes after ICH. Aim 2: To determine the molecular mechanism by which selective HDAC3 inhibition confers neuroprotection after ICH. Aim 3: To determine the functional role of microglial/macrophage HDAC3 in modulating secondary brain injury, hematoma resolution, and neurobehavioral outcomes after ICH. The proposed studies include a rigorous pharmacological and transgenic approach, including newly developed myeloid as well as microglia-specific HDAC3 conditional knockouts and a next-generation technique (CUT and Tag assay). The proposed project would determine for the first time (1) the therapeutic potential of selectively inhibiting HDAC3 in attenuating secondary brain damage and improving hematoma resolution and neurological outcomes after ICH (2) whether Nrf2 signaling is critical for the neuroprotection conferred via HDAC3 inhibition after ICH (3) gene-specific histone acetylation changes in microglia/macrophages upon HDAC3 inhibition after ICH and (4) the functional role of macrophage and microglia-specific expression of HDAC3 in modulating secondary brain damage, hematoma resolution and neurological outcomes after ICH. Altogether, the proposed project would identify clinically relevant molecular targets for therapeutic intervention for ICH.

继发性脑损伤是脑出血（ICH）后神经功能缺损的主要原因， 没有有效治疗的亚型。尽管表观遗传机制在复杂的 脑出血的病理生理学，组蛋白脱乙酰酶（HDAC）的亚型特异性作用或脑出血的精确分子机制， 组蛋白去乙酰化酶抑制剂（HDACi）介导的脑出血后神经保护作用的机制尚未明确。 根据我们最近的发现和令人信服的初步观察，我们的中心假设是， HDAC同种型，HDAC 3，是继发性脑损伤的关键分子调节剂，因此，神经损伤， 通过调节Nrf 2信号传导来改善ICH后的预后。为了检验这一假设，提出了三个具体目标。 目的1：确定HDAC 3的药理学抑制减弱继发性脑损伤并改善脑损伤的程度。 脑出血后血肿消退和神经行为结局。目的2：探讨其分子机制 选择性HDAC 3抑制通过其赋予ICH后的神经保护。目标3：确定职能作用 小胶质细胞/巨噬细胞HDAC 3在调节继发性脑损伤、血肿消退和 脑出血后的神经行为结局。拟议的研究包括严格的药理学和转基因 方法，包括新开发的骨髓以及小胶质细胞特异性HDAC 3条件性敲除和 下一代技术（CUT和Tag检测）。该项目将首次确定（1） 选择性抑制HDAC 3在减轻继发性脑损伤和改善脑损伤方面的治疗潜力 脑出血后血肿消退和神经系统结局（2）Nrf 2信号传导是否对脑出血后血肿消退和神经系统结局至关重要。 脑出血（3）基因特异性组蛋白乙酰化改变后，通过HDAC 3抑制提供的神经保护作用， （4）ICH后HDAC 3抑制对小胶质细胞/巨噬细胞的功能作用， HDAC 3的小胶质细胞特异性表达在调节继发性脑损伤、血肿消退和 脑出血后的神经学结局。总之，拟议的项目将确定临床相关的分子 ICH治疗干预的目标。