The Translocator Protein (TSPO) and Intracerebral Hemorrhage

脑出血（ICH）是一种无有效治疗的卒中亚型。小胶质细胞和脑浸润 巨噬细胞通过调节先天性免疫应答在ICH的病理生理学中起关键作用， 血肿消退是ICH后继发性脑损伤和功能恢复的关键决定因素。我们 最近的研究表明，18 kDa转运蛋白（TSPO）在小胶质细胞中的表达增加， 脑出血后的脑浸润巨噬细胞。然而，尽管TSPO在神经炎症中普遍存在， TSPO在小胶质细胞和巨噬细胞中的精确功能作用在很大程度上仍不清楚。基于我们 令人信服的初步研究，我们的中心假设是，小胶质细胞和巨噬细胞的特异性表达， TSPO调节氯化血红素诱导的继发性脑损伤并增强ICH后血肿消退到 为了验证这一点，提出了三个具体目标。目标1.检验TSPO基因缺失增加 继发性脑损伤并加重ICH后的神经系统结局。拟议的研究将包括 采用新开发的骨髓和小胶质细胞特异性TSPO条件性 击倒对手。目标2.测试小胶质细胞和巨噬细胞特异性表达TSPO增强TSPO表达的假设。 血肿消退和药物激活TSPO可改善ICH后的神经功能结局。的 结合遗传学和药理学方法的拟议研究将确定TSPO的作用 小胶质细胞/巨噬细胞介导的吞噬作用和改善ICH后的功能结局。目标3。测试 假设TSPO是用于体内检测活化的小胶质细胞/浸润的可行的分子靶标 巨噬细胞。鉴于TSPO表达的增加主要局限于活化的 脑出血后小胶质细胞和浸润性巨噬细胞，TSPO的第二代放射性标记配体，[125 I]碘- 将采用DPA-713，并通过非侵入性SPECT（单光子发射计算机断层扫描）监测TSPO-放射性配体结合。 光子发射计算机断层扫描）成像。拟议的项目将首先确定 时间的精确功能作用的小胶质细胞和巨噬细胞特异性表达的TSPO在继发性脑 ICH后的损伤、血肿消退和功能结局。此外，拟定的临床前研究 这也将首次验证靶向TSPO在改善神经功能方面的治疗潜力， 结果及其在脑出血后神经影像学应用中的诊断潜力。

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.