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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061642-02
Application #
7647340
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2008-07-01
Project End
2013-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$367,500
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
Rochaix, Jean-David (2013) Plant science. Fine-tuning photosynthesis. Science 342:50-1
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

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