Glutaminase and its neurotoxic link to HAND

谷氨酰胺酶及其与 HAND 的神经毒性联系

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：尽管抗逆转录病毒疗法有效，但影响艾滋病毒感染的人（手）会影响艾滋病毒感染的个体。抗逆转录病毒治疗后，手的患病率和神经认知功能障碍的不完全逆转呼吁采用新型的治疗方法。在手工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是一种基本的HIV-1病毒蛋白，在手推车病毒控制的个体的脑脊液中呈现。此外，小鼠中大脑特异性的HIV蛋白TAT表达模仿后卡特时代的手部病理学的关键方面，这表明TAT可能导致接受购物车的患者持续的中枢神经系统并发症。已知TAT通过兴奋性机制引起神经元损伤。此外，与未感染的对照相比，受HIV-1感染的患者在血浆和脑脊液中的谷氨酸浓度明显更高。谷氨酸水平升高破坏了大脑中正常的神经传递，导致HIV-1感染的神经发病发生。在过去的十年中，我们确定阻止谷氨酸（GLS）的活性，一种用于产生谷氨酸的主要酶，可以减轻巨噬细胞和小胶质细胞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功能的催化作用。此外，我们已经观察到巨噬细胞，小胶质细胞和神经元通过可能导致神经元损伤的未识别机制而引人入胜的GL释放。细胞外蔬菜（EV）（包括微泡和外泌体）已成为GLS释放的重要细胞机制。因此，在当前的建议中，我们假设含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中的关键致病事件。此外，我们假设通过GLS抑制剂异常更新/释放的GL可以具有治疗作用。将提供信息，因为GLS的大脑特异性过表达是否足以诱导大脑感染，损害小鼠的合成完整性和认知，以及GLS基因的巨噬细胞特异性有条件敲除以及含GLS的微测中释放的障碍物可以在TAT转基因小鼠模型中保护神经元功能。此外，将评估新型水溶性GLS抑制剂的治疗潜力。阐明GLS失调及其对手的病理生理学的贡献将有助于开发潜在的新型药物来治疗手和其他神经退行性疾病。