Neural progenitor cells (NPC) are present throughout life and replenish neurons and glia (astrocytes and oligodendrocytes) through neurogenesis, a process that requires proper migration, proliferation and differentiation of NPC. Neurogenesis appears to be dysfunctional in neurodegenerative disorders including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases, where dead or injured neurons are not replaced. HAD is a neurodegenerative disorder where HIV-1-infected and activated brain mononuclear phagocytes (MP;perivascular macrophages and microglia) mediate inflammatory conditions that alter brain homeostasis. We recently demonstrated that HIV-1-infected and activated macrophages inhibit neurogenesis but enhance gliogenesis. We propose this gliogenesis is mediated through brain inflammation attributable to the dysregulation of stromal cell-derived factor 1 (SDF-1). SDF-1 is an endogenous ligand for the chemokine receptor, CXCR4, which is highly expressed on human NPC and mediates NPC migration. Improper SDF-1 and CXCR4 function can affect neural repair by impairing NPC migration. SDF-1 is released in response to glial activation, mediated by inflammatory cytokines from HIV-1-infected and activated MP such as Interleukin one beta (IL-12). SDF-1 is elevated in the cerebrospinal fluid of HAD patients. Activated matrix metalloproteinase-2 (MMP-2) is produced by HIV-1 infected and activated MP and cleaves SDF-1 resulting in a neurotoxic fragment. This proposal will examine the role of HIV-1-infected and activated macrophage in brain inflammation and their effects on neurogenesis. We hypothesize HIV-1-infected and immune- activated MP inhibit neuronal differentiation and promote gliogenesis. Specifically, we propose this shift in neurogenesis is dependent upon SDF-1 produced by activated astrocytes. This gliogenesis may be a consequence of modification/degradation of SDF-1 by factors released from HIV-1-infected MP leading to impairment of normal SDF-1/CXCR4 mediated NPC migration, survival, proliferation and differentiation, generating an environment detrimental to CNS repair. Using our human NPC culture system in a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, this project will mimic HIV-1-infection and immune-activation of brain MP and investigate the effect of CNS inflammation on neurogenesis. Elucidating the mechanisms of SDF-1/CXCR4 influence on neurogenesis may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.
Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-associated dementia (HAD). This work will elucidate mechanisms through which neurogenesis is affected by HAD, which could identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.
|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|
|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|
|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|
|Wang, Yongxiang; Tian, Changhai; Zheng, Jialin C (2013) FoxO3a contributes to the reprogramming process and the differentiation of induced pluripotent stem cells. Stem Cells Dev 22:2954-63|
|Chen, E; Xu, D; Lan, X et al. (2013) A novel role of the STAT3 pathway in brain inflammation-induced human neural progenitor cell differentiation. Curr Mol Med 13:1474-84|
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