Glutaminase and its neurotoxic link to HAND

谷氨酰胺酶及其与 HAND 的神经毒性联系

• 批准号: 9146113
• 负责人: Jialin Charles Zheng
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146113
• 关键词: Acute; Affect; Animal Model; Brain; Cell membrane; Cerebrospinal Fluid; Cognition; Critical Pathways; Data; Disease; Drug Targeting; Effectiveness; Elderly man; Encephalitis; Enzymes; Event; Functional disorder; Generations; Genes; Genetic; Glutamates; Glutaminase; Glutamine; HIV; HIV tat Protein; HIV-1; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Licensing; Link; Lipids; Lymphoid; Mediating; Memory; Metabolism; Microglia; Mitochondria; Molecular; Mus; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neuropathogenesis; Nucleic Acids; Organ; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Prevalence; Production; Proteins; Regulation; Role; Secretory Vesicles; Signaling Molecule; Synapses; Synaptic Transmission; Tamoxifen; Therapeutic; Therapeutic Effect; Transgenic Mice; Transgenic Organisms; United Kingdom; Viral Proteins; Water; antiretroviral therapy; cell type; clinical application; cognitive function; combat; diabetic; effective therapy; esophagus ulcer; exosome; extracellular; extracellular vesicles; immune activation; improved; in vivo; inhibitor/antagonist; macrophage; microvesicles; mouse model; nervous system disorder; neurocognitive disorder; neuroinflammation; neurotoxic; neurotoxicity; neurotransmission; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; pre-clinical; prevent; public health relevance; relating to nervous system; response; tumor progression; vesicular release

 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.

 描述（由申请人提供）：尽管抗逆转录病毒治疗有效，但影响 HIV 感染者的 HIV 相关神经认知障碍 (HAND) 持续增加。 HAND 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需要新的治疗方法。在 HAND 的各种病理生理学中，突触功能障碍可能是认知障碍的基础。有趣的是，Tat 是一种重要的 HIV-1 病毒蛋白，存在于接受 cART 病毒学控制的个体的脑脊液中。此外，小鼠脑特异性 HIV 蛋白 Tat 表达模拟了后 cART 时代 HAND 病理学的关键方面，表明 Tat 可能是接受 cART 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引起神经元损伤。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谷氨酸浓度显着较高。谷氨酸水平升高会扰乱大脑中的正常神经传递，导致 HIV-1 感染的神经发病机制。在过去的十年中，我们已经确定，阻断谷氨酰胺酶（GLS）（一种产生谷氨酸的主要酶）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症对巨噬细胞、小胶质细胞和神经元 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不明机制释放 GLS，可能导致神经元损伤。细胞外囊泡 (EV)，包括微泡和外泌体，已成为 GLS 释放的重要细胞机制。因此，在当前的提议中，我们假设含有 GLS 的 EV 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 可能对 HAND 具有治疗作用。将提供以下信息：GLS 的脑特异性过度表达是否足以诱发脑部炎症、损害小鼠的突触完整性和认知，以及巨噬细胞特异性条件性敲除 GLS 基因并阻断含有 GLS 的微泡释放是否可以保护 Tat 转基因小鼠模型中的神经元功能。此外，新型水溶性 GLS 抑制剂将在 HAND 相关动物模型中评估其治疗潜力。 GLS 失调及其对 HAND 病理生理学的贡献的阐明将有助于开发用于治疗 HAND 和其他神经退行性疾病的潜在新药。