Heme Oxygenase-1 as a novel therapeutic target in HIV-mediated neurodegeneration

描述(由申请人提供)：艾滋病毒感染导致认知、运动和行为缺陷，统称为艾滋病毒相关性神经认知障碍(HAND)。尽管接受了抗逆转录病毒治疗，但仍有约50%的HIV患者继续出现神经认知障碍，这证实了辅助治疗的必要性。临床研究表明，手部神经认知障碍与中枢神经系统巨噬细胞/小胶质细胞激活有关。活化的和HIV感染的单核细胞来源的巨噬细胞(HIV-MDM)和小胶质细胞通过可溶性因子介导手部神经病理，包括引起神经元损伤的兴奋性神经毒素如谷氨酸。手足口病患者的脑脊液中谷氨酸水平升高，这与神经认知障碍和脑萎缩的程度有关。识别调节HIV-MDM中神经毒素释放的内源性途径，特别是谷氨酸，可能为手部神经变性提供重要的治疗靶点。体内氧化应激标志物与HIV+患者的神经认知损害相关。我们已经明确证明，血红素加氧酶-1(HO-1)，前哨细胞保护性抗氧化反应蛋白，是HIV-MDM神经毒性的关键调节因子。HO-1在HIV-MDM中被显著抑制，并与谷氨酸的产生和神经毒素的释放有关。相反，HO-1在HIV-MDM中的诱导减少了神经毒素的释放，表明HO-1是一种新的治疗靶点。我们发现HO-1在HIV+患者的前额叶皮质表达减少。大脑中这种HO-1抑制与执行域神经认知障碍、中枢神经系统病毒负荷和巨噬细胞激活相关。我们将评估HO-1在扩大的脑区的区域表达，以确定与相关神经认知领域和艾滋病毒疾病进展标志的相关性。我们还将通过分析HO-1mRNA和蛋白的表达及其稳定性来探讨目前未知的HO-1在HIV-MDM中的抑制机制。最后，我们将在以前工作的基础上进一步确定HO-1诱导减少HIV-MDM神经毒素产生的治疗潜力。特别是，我们将研究富马酸酯(FAE)，包括富马酸二甲酯(DMF)，作为潜在的治疗候选化合物。DMF通过ARE诱导HO-1，穿过血脑屏障，并已在多发性硬化症III期临床试验中被证明减少神经炎症。DMF在MS试验中的安全性和有效性，它们的抗炎特性，它们对HO-1的诱导，都突显了它们的治疗潜力。我们假设，HIV+患者中枢神经系统中HIV驱动的HO-1抑制驱动巨噬细胞介导的神经变性，通过FAES(如DMF)逆转这种HO-1缺陷将改善这种神经退化。

DESCRIPTION (provided by applicant): HIV infection causes cognitive, motor, and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND). Despite antiretroviral therapy, ~50% of HIV patients continue to develop neurocognitive impairment, affirming a need for adjunctive therapy. Clinical studies have shown that neurocognitive impairment in HAND correlates with CNS macrophage/microglia activation. Activated and HIV-infected monocyte-derived macrophages (HIV-MDM) and microglia mediate HAND neuropathology through soluble factors, including excitatory neurotoxins like glutamate, which induce neuronal injury. HAND patients have increased levels of glutamate in their CSF, which correlates with the degree of neurocognitive impairment and brain atrophy. Identification of endogenous pathways that regulate neurotoxin release, particularly glutamate, in HIV-MDM may provide important therapeutic targets for neurodegeneration in HAND. In vivo markers of oxidative stress correlate with neurocognitive impairment in HIV+ patients. We have specifically demonstrated that heme oxygenase-1 (HO-1), the sentinel cytoprotective antioxidant response protein, is a key regulator of HIV-MDM neurotoxicity. HO-1 is strikingly suppressed in HIV-MDM and correlates to glutamate production and neurotoxin release. In contrast, HO-1 induction in HIV-MDM decreases neurotoxin release, suggesting HO-1 as a novel therapeutic target in HAND. We found HO-1 expression to be decreased in the prefrontal cortex of HIV+ patients. This HO-1 suppression in the brain correlates with executive domain neurocognitive impairment, CNS viral load, and macrophage activation. We will evaluate the regional expression of HO-1 in an expanded panel of brain regions to determine correlations to relevant neurocognitive domains and markers of HIV disease progression. We will also investigate the currently unknown mechanism of HO-1 suppression in HIV-MDM through analysis of HO-1 mRNA and protein expression and stability. Lastly, we will expand upon our previous work to further define the therapeutic potential for HO-1 induction in reducing HIV-MDM neurotoxin production. Particularly, we will study the fumaric acid esters (FAEs), including dimethyl fumarate (DMF), as potential therapeutic candidates. DMF induces HO-1 through the ARE, cross the blood brain barrier, and has been shown to decrease neuroinflammation in multiple sclerosis phase III clinical trials. The safety and efficacy of DMF in MS trials, their anti-inflammatory properties, their induction of HO-1 underscore their therapeutic potential in HAND. We hypothesize that HIV-driven suppression of HO-1 in the CNS of HIV+ patients drives macrophage-mediated neurodegeneration and that reversal of this HO-1 deficiency through FAEs such as DMF will ameliorate this neurodegeneration.