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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：
9357733
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/9357733
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 Ulcer United Kingdom Viral Proteins Water antiretroviral therapy cell type clinical application cognitive function combat diabetic 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.