HDAC3 as a therapeutic target for intracerebral hemorrhage

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.