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：
9700732
负责人：
Howard E Gendelman
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9700732
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 Impairment In Vitro Individual Infection Inflammation Inflammatory Knock-out Knockout Mice Laboratories Lead Learning Link Lipids Lymphoid Mediating Memory Metabolism Microglia Mitochondria Molecular Mus Neuraxis Neurocognitive Neurodegenerative Disorders Neuronal Injury Neurons Neuropathogenesis Nucleic Acids Organ Pathogenicity Pathology Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Plasma Prevalence Production Proteins Regulation Role Secretory Vesicles Signaling Molecule Synapses Synaptic Transmission Tamoxifen Therapeutic Therapeutic Effect Transgenic Mice Transgenic Organisms Type 2 diabetic Ulcer United Kingdom Viral Proteins Water antiretroviral therapy cell type clinical application cognitive function combat conditional knockout effective therapy excitotoxicity exosome extracellular extracellular vesicles immune activation improved in vivo inhibitor/antagonist macrophage microvesicles mouse model nervous system 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 virology

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 的患病率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，Tat 是一种重要的 HIV-1 病毒蛋白，存在于 HAND 中。此外，小鼠脑特异性 HIV 蛋白 Tat 的表达模拟了后 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。众所周知，Tat 会通过兴奋性毒性机制引起神经元损伤，此外，与未感染者相比，HIV-1 感染者的血浆和脑脊液中谷氨酸浓度显着升高。谷氨酸水平升高会扰乱大脑中的正常神经传递，从而导致 HIV-1 感染的神经发病机制。在过去的十年中，我们已经确定，谷氨酰胺酶 (GLS)（一种产生谷氨酸的主要酶）的活性会受到抑制。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中 GLS 功能的因果影响。此外，我们还观察到了有趣的释放。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知机制，包括微泡和外泌体，已成为 GLS 释放的重要细胞机制。，我们发现含有 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。通过 GLS 抑制剂异常上调/释放的 GLS 可能对 HAND 具有治疗作用，将提供以下信息：GLS 的大脑特异性过度表达是否足以诱导大脑炎症、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是否有效。 GLS 基因和阻断含有 GLS 的微泡释放可以保护 HAND 的 Tat 转基因小鼠模型中的神经元功能。此外，还将评估新型水溶性 GLS 抑制剂。阐明 GLS 失调及其对 HAND 病理生理学的贡献将有助于开发治疗 HAND 和其他神经退行性疾病的潜在新药。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Urban airborne PM2.5-activated microglia mediate neurotoxicity through glutaminase-containing extracellular vesicles in olfactory bulb.

城市空气中 PM2.5 激活的小胶质细胞通过嗅球中含有谷氨酰胺酶的细胞外囊泡介导神经毒性。

DOI：
发表时间：
2020-09
期刊：
影响因子：
0
作者：
Chen, Xiaoyu;Guo, Jing;Huang, Yunlong;Liu, Shan;Huang, Ying;Zhang, Zezhong;Zhang, Fang;Lu, Zhongbing;Li, Fang;Zheng, Jialin C;Ding, Wenjun
通讯作者：
Ding, Wenjun

[Not Available].

[无法使用]。

DOI：
发表时间：
2019-08-15
期刊：
影响因子：
3.3
作者：
Liu, Jianhui;Li, Yuju;Xia, Xiaohuan;Yang, Xiaoyu;Zhao, Runze;Peer, Justin;Wang, Hongyun;Tong, Zenghan;Gao, Fengtong;Lin, Hai;Wu, Beiqing;Huang, Yunlong;Zheng, Jialin C
通讯作者：
Zheng, Jialin C

Safety, Tolerability, and Immunogenicity of COVID-19 Vaccines: A Systematic Review and Meta-Analysis.

COVID-19 疫苗的安全性、耐受性和免疫原性：系统评价和荟萃分析。