Brain inflammation underlies the neuropathogenesis of HIV-1 infection. The inflammatory mechanism driving neurological disease and neuronal injury affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory and neurotoxic mediator implicated in the pathogenesis of HAD is glutaminase. Glutaminase catalyzes the deamination of glutamine to glutamate and is generally localized to the inner membrane of the mitochondria. Recently, we demonstrated that glutamate is upregulated by HIV-infected, immune-activated monocyte derived macrophages (MDM) and this neurotoxic increase in glutamate represents a major contribution to macrophage-mediated neurotoxicity. Importantly, glutaminase activity is required for glutamate production, and glutaminase-specific siRNA and small-molecule glutaminase inhibitors effectively prevent excess glutamate production. Moreover, the glutaminase isoform glutaminase C (GAC) is upregulated in HIV-1-infected MDM, and GAC release may be involved in increased glutamate production. HIV-1 infection also decreases the levels of expression of microRNA-23a/b, a glutaminase-targeting member of non- coding RNAs, in HIV-1 infected MDM. Further, cytokines such as TNF-1 and IFN-1, produced by HIV-1-infected and immune-activated macrophages increase glutaminase isoform kidney type glutaminase (KGA) expression in neurons, which could potentiate macrophage mediated neurotoxicity during HIV-1 infection. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important event in HAD is the increase of glutaminase expression and release, mediated by inflammation and mitochondria stress during HIV- 1 infection. We argue that this is a significant pathogenic event that triggers macrophage-neuron interactions and affects signaling events eventually leading to increased brain glutamate levels and excitotoxic neuronal damage. This project will develop assays that investigate brain macrophage activation, miRNA23a/b regulation, mitochondrial stress and neuronal injury that occur in HAD. A drug delivery system including a copolymer conjugated with glutaminase and mitochondrial stress inhibitors will be examined in a severe combined immune deficient HIV-1 encephalitis mouse model. The elucidation of the mechanisms by which glutaminase mediates neuronal injury during HIV-1 infection will aid in developing potential new therapeutic agents and drug delivery systems for the treatment of HAD.
Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-1 associated neurocognitive disorders (HAND). This work will elucidate mechanisms through which glutaminase play in neuronal injury during HAND, which could identify new therapeutic strategies for treating HAND and other neurodegenerative disorders.
|Wang, Y; Xu, P; Qiu, L et al. (2016) CXCR7 Participates in CXCL12-mediated Cell Cycle and Proliferation Regulation in Mouse Neural Progenitor Cells. Curr Mol Med 16:738-746|
|Liu, Fang; Huang, Yunlong; Zhang, Fang et al. (2015) Macrophages treated with particulate matter PM2.5 induce selective neurotoxicity through glutaminase-mediated glutamate generation. J Neurochem 134:315-26|
|Lai, Siqiang; Zhang, Min; Xu, Dongsheng et al. (2015) Direct reprogramming of induced neural progenitors: a new promising strategy for AD treatment. Transl Neurodegener 4:7|
|Tian, Changhai; Li, Yuju; Huang, Yunlong et al. (2015) Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion. Sci Rep 5:12622|
|Chen, Qiang; Zhang, Min; Li, Yuju et al. (2015) CXCR7 Mediates Neural Progenitor Cells Migration to CXCL12 Independent of CXCR4. Stem Cells 33:2574-85|
|Wu, Beiqing; Huang, Yunlong; Braun, Alexander L et al. (2015) Glutaminase-containing microvesicles from HIV-1-infected macrophages and immune-activated microglia induce neurotoxicity. Mol Neurodegener 10:61|
|Wang, M Q; Huang, Y L; Huang, J et al. (2015) RIG-I detects HIV-1 infection and mediates type I interferon response in human macrophages from patients with HIV-1-associated neurocognitive disorders. Genet Mol Res 14:13799-811|
|Zhang, Min; Song, Aihong; Lai, Siqiang et al. (2015) Applications of stripe assay in the study of CXCL12-mediated neural progenitor cell migration and polarization. Biomaterials 72:163-171|
|Wang, Yi; Huang, Yunlong; Zhao, Lixia et al. (2014) Glutaminase 1 is essential for the differentiation, proliferation, and survival of human neural progenitor cells. Stem Cells Dev 23:2782-90|
|Tian, Changhai; Liu, Qiang; Ma, Kangmu et al. (2013) Characterization of induced neural progenitors from skin fibroblasts by a novel combination of defined factors. Sci Rep 3:1345|
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