Intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Microglia and brain-infiltrating macrophages play critical roles in the pathophysiology of ICH by regulating innate immune response and hematoma resolution, the key determinants of secondary brain damage and functional recovery after ICH. Our recent studies demonstrated an augmented expression of 18kDa translocator protein (TSPO) in microglia and brain infiltrating macrophages after ICH. However, despite the prevalence of TSPO in neuroinflammation, the precise functional role of TSPO in microglia and macrophages remains largely unclear. Based on our compelling preliminary studies, our central hypothesis is that microglia and macrophage-specific expression of TSPO modulates hemin-induced secondary brain damage and enhances hematoma resolution after ICH. To test this, three specific aims are proposed.
Aim 1. Test the hypothesis that genetic deletion of TSPO augments secondary brain damage and exacerbates neurological outcomes after ICH. The proposed studies will include a rigorous transgenic approach employing newly developed myeloid and microglia-specific TSPO conditional knockouts.
Aim 2. Test the hypothesis that microglia and macrophage- specific expression of TSPO enhances hematoma resolution and pharmacological activation of TSPO improves neurological outcomes after ICH. The proposed studies incorporating both genetic and pharmacological approaches will determine the role of TSPO in microglia/macrophage-mediated phagocytosis and improving functional outcomes after ICH.
Aim 3. Test the hypothesis that TSPO is a feasible molecular target for the in vivo detection of activated microglia/infiltrating macrophages after ICH. Given that the increased expression of TSPO is primarily localized to activated microglia and infiltrating macrophages after ICH, a second generation radio labeled ligand for TSPO, [125I]iodo- DPA-713 will be employed and TSPO-radio ligand binding will be monitored by non-invasive SPECT (Single- photon emission computed tomography) imaging after ICH. The proposed project would identify for the first time the precise functional role of microglia and macrophage- specific expression of TSPO in secondary brain damage, hematoma resolution and functional outcomes after ICH. Further, the proposed preclinical studies would also validate for the first time the therapeutic potential of targeting TSPO in improving neurological outcomes and its diagnostic potential for neuroimaging applications after ICH.
Intracerebral hemorrhage (ICH) is a major public health problem. Given the role of microglia or macrophages in ICH-induced secondary brain damage and functional recovery, if the hypotheses of this proposal are confirmed, the data from this grant will identify clinically relevant molecular targets for therapeutic intervention and develop a non-invasive neuroimaging tool for monitoring inflammatory responses after ICH.
