Millions of HIV-infected human patients suffer chronic pain. However, the pathological process leading to this devastating neurological condition is unclear, and an effective therapy is not available. Our long-term goals are to better understand the mechanism of HIV-associated pain and to develop rationale-based effective therapies. The objective of this application is to determine the role of glia, especially astrocytes, in the neuropathogenesis of HIV pain. In preliminary studies, we found that the HIV patients who developed chronic pain manifested dramatic astrocyte activation in the spinal cord dorsal horn (SCDH);this was not seen in the HIV patients who otherwise were similar but did not experience chronic pain. In this study, we aim to elucidate the mechanism and pathological significance of the astrocyte activation during the development of HIV gp120 (a major HIV neurotoxin protein)-induced pain in the mouse model. We propose that gp120 activates astrocytes in the SCDH through a mechanism that involves a neuron-to-astrocyte signaling protein, Wnt5a, and that the Wnt5a- regulated astrocyte activation promotes the development of gp120-induced pain. This hypothesis will be tested in three Specific Aims.
In Aim #1, we will determine the requirement of neuronal Wnt5a in the SCDH for gp120 to induce astrocyte activation.
In Aim #2, we will test the idea that Wnt5a activates astrocytes by stimulating a ROR2/JNK signaling pathway.
In Aim #3, we will determine the involvement of Wnt5a-regulated astrocyte activation in the pathogenesis of gp120-induced pain in mice. The proposed research will use an integrated multidisciplinary approach of molecular and cell biology, pharmacology and conditional gene knockout. The results will provide important insights into the mechanism of astrocyte activation and its pathogenic role in HIV- associated chronic pain. The knowledge obtained is expected to facilitate the development of rationale-based medicine for HIV-associated chronic pain.

Public Health Relevance

HIV patients often suffer from chronic pain. This project will help us better understand how HIV may cause pain-related problems in the spinal cord so that effective therapies can be designed to block the pathogenic processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079166-01A1
Application #
8467551
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2012-09-15
Project End
2017-05-31
Budget Start
2012-09-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Yang, Yi; Liu, Xiaokang; Wu, Ting et al. (2018) Quercetin attenuates AZT-induced neuroinflammation in the CNS. Sci Rep 8:6194
Yuan, Subo; Shi, Yuqiang; Guo, Kaiwen et al. (2018) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice. J Neuroimmune Pharmacol 13:230-236
Bae, Chilman; Wang, Jigong; Shim, Hyun Soo et al. (2018) Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice. Mol Pain 14:1744806918797032
Zhang, Wenping; Shi, Yuqiang; Peng, Yanxi et al. (2018) Neuron activity-induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem 293:15641-15651
Tang, Shao-Jun (2017) Potential Role of Phase Separation of Repetitive DNA in Chromosomal Organization. Genes (Basel) 8:
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78
Wu, Ting; Zhang, Juan; Geng, Mingxing et al. (2017) Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. Sci Rep 7:4117
Tang, Shao-Jun (2017) New Evidence for the Theory of Chromosome Organization by Repetitive Elements (CORE). Genes (Basel) 8:
Ru, Wenjuan; Tang, Shao-Jun (2017) HIV-associated synaptic degeneration. Mol Brain 10:40
Wang, Yongdi; Liao, Jinxu; Tang, Shao-Jun et al. (2017) HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/?-Catenin Signaling Pathway. J Mol Neurosci 62:199-208

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