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.
Excess glutamate is known to cause synaptic dysfunctions and neuronal injury in HIV-associated neurocognitive disorder (HAND). We will investigate a novel approach targeting glutaminase, which is a primary enzyme for the production of glutamate in the brain, to block excess glutamate production. Inhibition of glutaminase through novel inhibitors may become a novel strategy to prevent neuronal injury in HAND.
|Wu, Beiqing; Liu, Jianhui; Zhao, Runze et al. (2018) Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate. J Neuroinflammation 15:79|
|Huang, Yunlong; Li, Yuju; Zhang, Hainan et al. (2018) Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Cell Discov 4:19|
|Ma, Kangmu; Deng, Xiaobei; Xia, Xiaohuan et al. (2018) Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons. Transl Neurodegener 7:29|
|He, Miao; Zhang, Hainan; Li, Yuju et al. (2018) Cathelicidin-Derived Antimicrobial Peptides Inhibit Zika Virus Through Direct Inactivation and Interferon Pathway. Front Immunol 9:722|
|Wang, Yi; Li, Yuju; Zhao, Runze et al. (2017) Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice. Brain Behav Immun 66:135-145|
|Wang, Kaizhe; Ye, Ling; Lu, Hongfang et al. (2017) TNF-? promotes extracellular vesicle release in mouse astrocytes through glutaminase. J Neuroinflammation 14:87|
|Smith, Derek K; He, Miao; Zhang, Chun-Li et al. (2017) The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders. Prog Neurobiol 157:212-229|
|Li, Yuju; Peer, Justin; Zhao, Runze et al. (2017) Serial deletion reveals structural basis and stability for the core enzyme activity of human glutaminase 1 isoforms: relevance to excitotoxic neurodegeneration. Transl Neurodegener 6:10|
|Zhang, Min; Qiu, Lisha; Zhang, Yanyan et al. (2017) CXCL12 enhances angiogenesis through CXCR7 activation in human umbilical vein endothelial cells. Sci Rep 7:8289|
|Xu, Peipei; Wang, Yingchun; Qin, Zhao et al. (2017) Combined Medication of Antiretroviral Drugs Tenofovir Disoproxil Fumarate, Emtricitabine, and Raltegravir Reduces Neural Progenitor Cell Proliferation In Vivo and In Vitro. J Neuroimmune Pharmacol 12:682-692|
Showing the most recent 10 out of 11 publications