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）中风后神经功能缺损的主要原因