Glutaminase and its neurotoxic link to HAND

 描述(申请人提供)：尽管抗逆转录病毒治疗有效，但影响艾滋病毒感染者的艾滋病毒相关神经认知障碍(HAND)继续增加。手部疾病的流行和抗逆转录病毒治疗后神经认知功能障碍的不完全逆转要求采用新的治疗方法。在手的各种病理生理学机制中，突触功能障碍可能是认知障碍的基础。有趣的是，Tat是一种基本的HIV-1病毒蛋白，存在于由病毒控制的CART患者的脑脊液中。此外，小鼠大脑特异性HIV蛋白TAT的表达模拟了后CART时代手部病理的关键方面，表明TAT可能是接受CART的患者持续中枢神经系统并发症的原因。已知TAT通过兴奋性毒性机制导致神经元损伤。此外，与未感染的对照组相比，HIV-1感染患者的血浆和脑脊液中的谷氨酸浓度明显更高。谷氨酸水平的升高扰乱了大脑中正常的神经传递，导致了HIV-1感染的神经发病机制。在过去的十年中，我们已经证实，阻断谷氨酰胺酶(GLS)的活性可以减轻巨噬细胞和小胶质细胞的神经炎症和神经毒性反应。我们已经证明了先天免疫激活和促炎对巨噬细胞、小胶质细胞和神经元中GLS功能的因果影响。此外，我们还观察到巨噬细胞、小胶质细胞和神经元通过未知的机制释放GLS，这可能导致神经元损伤(S)。细胞外小泡(EVS)是GLS释放的重要细胞机制，包括微泡和外切体。因此，在目前的方案中，我们假设含有GLS的EVS的释放是HIV-1介导的神经元损伤和海马突触功能障碍的关键致病事件。此外，我们假设，通过GLS抑制剂阻断异常上调/释放的GLS可能会有治疗效果。在TAT转基因小鼠的手部模型中，脑特异性GLS的过度表达是否足以引起脑部炎症，损害突触完整性和认知能力，以及巨噬细胞特异性条件性敲除GLS基因和阻断含有GLS的微囊释放是否可以保护神经元功能等信息将被提供。此外，将在与手相关的动物模型中评估新型水溶性GLS抑制剂的治疗潜力。阐明GLS失调及其在手部病理生理学中的作用将有助于开发潜在的治疗手部和其他神经退行性疾病的新药物。

 DESCRIPTION (provided by applicant): Despite the effectiveness of antiretroviral therapy, HIV-associated neurocognitive disorders (HAND) that affect HIV infected individuals continue to increase. The prevalence of HAND and the incomplete reversal of neurocognitive dysfunctions after antiretroviral therapy have called for novel therapeutic approaches. Among the various pathophysiology of HAND, synaptic dysfunction likely underlies cognitive impairments. Interestingly, Tat, an essential HIV-1 viral protein, is present in the cerebrospinal fluid of individuals virologically controlled on cART. Furthermore, Brain-specific HIV protein Tat expression in mice mimics key aspects of HAND pathology in the post-cART era, suggesting that Tat may be responsible for the sustained central nervous system complications in patients receiving cART. Tat is known to cause neuronal injury via excitotoxic mechanisms. Furthermore, HIV-1-infected patients have significantly higher concentrations of glutamate in their plasma and cerebrospinal fluid compared to uninfected controls. Elevated levels of glutamate disrupt normal neural transmission in the brain, contributing to the neuropathogenesis of HIV-1 infection. In the past decade we have established that blocking the activity of glutaminase (GLS), a primary enzyme for the production of glutamate, could alleviate macrophages and microglia neuroinflammatory and neurotoxic response. We have demonstrated causal effects of innate immune activation and proinflammatory on the GLS function in macrophages, microglia, and neurons. Furthermore, we have observed an intriguing release of GLS by macrophages, microglia, and neurons, through unidentified mechanism(s) that could cause neuronal injury. Extracellular vesicles (EVs), which include microvesicles and exosomes, have emerged as an important cellular mechanism for GLS release. Therefore, in the current proposal, we hypothesize that the release of GLS-containing EVs is a critical pathogenic event in HIV-1-mediated neuronal injury and hippocampal synaptic dysfunction. Moreover, we hypothesize that blocking aberrantly upregulated/released GLS through GLS inhibitors could have therapeutic effects in HAND. Information will be provided as whether brain-specific overexpression of GLS is sufficient to induce brain inflammation, impair synaptic integrity and cognition in mice, and whether macrophage-specific conditional knockout of GLS gene and blocking of GLS-containing microvesicles release could protect neuronal function in a Tat transgenic mouse model of HAND. Furthermore, novel water-soluble GLS inhibitors will be evaluated for their therapeutic potentials in HAND relevant animal models. The elucidation of the GLS dysregulation and its contribution to pathophysiology of HAND will aid in developing potential novel agents for the treatment of HAND and other neurodegenerative disorders.