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(一种中风)后神经功能障碍的主要原因 没有有效治疗的亚型。尽管表观遗传机制在复合体中的作用正在显现 脑出血的病理生理学，组蛋白脱乙酰酶(HDACs)的异构体特异性作用或精确的分子 组蛋白脱乙酰酶抑制剂(HDACi)介导的脑出血后神经保护机制尚未明确。 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A类I HDAC亚型，HDAC3，是继发性脑损伤的关键分子调节因子，从而影响神经功能。 通过调节Nrf2信号转导脑出血后的预后。为了验证这一假设，本文提出了三个具体目标。 目的1：确定HDAC3的药理抑制减轻继发性脑损伤并改善 脑出血后血肿消退和神经行为结果。目的2：确定分子机制 选择性抑制HDAC3对脑出血后的神经保护作用。目标3：确定职能角色 小胶质/巨噬细胞HDAC3在调节继发性脑损伤、血肿消退和 脑出血后神经行为结局。拟议的研究包括严格的药理学和转基因 方法，包括新开发的髓系以及小胶质细胞特异性的HDAC3条件性基因敲除和 下一代技术(切割和标签分析)。拟议的项目将首次确定(1) 选择性抑制HDAC3在减轻和改善继发性脑损伤中的作用 脑出血后血肿的缓解和神经预后(2)Nrf2信号是否对脑出血 脑出血(3)基因特异性组蛋白乙酰化改变后通过抑制HDAC3发挥神经保护作用 小胶质细胞/巨噬细胞对脑出血后HDAC3的抑制作用以及(4)巨噬细胞和巨噬细胞的功能作用 小胶质细胞特异性表达HDAC3在调节继发性脑损伤、血肿消退和预后中的作用 脑出血后的神经学转归。总之，拟议的项目将确定临床上相关的分子 脑出血治疗干预的靶点。