Drug abuse and HIV-1 are two linked global health crises. Despite the recognized impact of cocaine abuse on the clinical course of HIV-1-associated neurological disorder (HAND), the mechanisms underlying the ability of cocaine to modulate central nervous system (CNS) pathology remain elusive. Neuroinflammation involving robust microglial activation has emerged as an important phenotype and correlate of HIV infection and drug abuse despite the advent of combined anti-retroviral therapy (cART). The underlying cause of HIV-associated neuroinflammation is likely attributable to the fact that following virus infection and formation of the proviral DNA, cART is ineffective in abrogating the expression of toxic viral gene products such as Tat and gp120, that continue to be present in tissues such as the CNS. Furthermore, similar to HIV positive subjects on cART, SIV- infected rhesus macaques on cART also demonstrate increased glial activation, which was shown to be associated with dysregulation of various signature microRNAs (miRs). Emerging evidence also points to the role of drugs such as cocaine in mediating glial activation with global changes in miRs. In fact, in a recent finding, we demonstrate that cocaine-mediated activation of microglia involves down-regulation of miR-124 expression both in vitro and in vivo. Furthermore, we have also elucidated that HIV Tat mediated microglial migration involves upregulated expression of miR-9 with a concomitant downregulation of its target, monocyte chemotactic protein-induced protein 1 (MCPIP1). We thus hypothesize that both cocaine and HIV Tat modulate increased microglial activation and migration respectively, via two distinct mechanisms: a) cocaine mediates downregulation of miR-124 via DNA methylation of its promoter, leading in turn, to increased TLR4 signaling that culminates into increased microglial activation and, b) exposure of microglia to HIV Tat upregulates the expression of miR-9 leading in turn, to enhanced microglial migration via downregulation of the target MCPIP1. Three experienced PIs (Drs. Buch, Hu, & Guo) will co-lead this project to accomplish the proposed goals. This proposal is responsive to the RFA (RFA-DA-16-012) focusing on epigenomic and non-coding RNA regulation in HIV/AIDS and substance abuse.

Public Health Relevance

Complications of CNS including neuroinflamamtion are exacerbated in cocaine abusing HIV-infected patients. Understanding mechanisms by which the two enhance complications of the CNS could have ramifications for future development of therapeutic interventions for treatment of neuroinflammation in HIV-infected cocaine abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA043138-04
Application #
9694651
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Satterlee, John S
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
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
Hu, Guoku; Liao, Ke; Niu, Fang et al. (2018) Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration. Mol Ther Nucleic Acids 13:450-463
Periyasamy, Palsamy; Liao, Ke; Kook, Yeon Hee et al. (2018) Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling. Mol Neurobiol 55:3196-3210
Guo, Ming-Lei; Kook, Yeon Hee; Shannon, Callen E et al. (2018) Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH. Cell Death Discov 4:22
Thangaraj, Annadurai; Periyasamy, Palsamy; Liao, Ke et al. (2018) HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy 14:1596-1619
Periyasamy, Palsamy; Thangaraj, Annadurai; Guo, Ming-Lei et al. (2018) Epigenetic Promoter DNA Methylation of miR-124 Promotes HIV-1 Tat-Mediated Microglial Activation via MECP2-STAT3 Axis. J Neurosci 38:5367-5383
Yang, Lu; Niu, Fang; Yao, Honghong et al. (2018) Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration. J Neuroimmune Pharmacol 13:330-344
Sil, Susmita; Niu, Fang; Tom, Eric et al. (2018) Cocaine Mediated Neuroinflammation: Role of Dysregulated Autophagy in Pericytes. Mol Neurobiol :
Hu, Guoku; Yelamanchili, Sowmya; Kashanchi, Fatah et al. (2017) Proceedings of the 2017 ISEV symposium on ""HIV, NeuroHIV, drug abuse, & EVs"". J Neurovirol 23:935-940
Hu, Guoku; Witwer, Kenneth W; Bond, Vincent C et al. (2017) Proceedings of the ISEV symposium on ""HIV, NeuroAIDS, drug abuse & EVs"". J Extracell Vesicles 6:1294360
Guo, Ming-Lei; Periyasamy, Palsamy; Liao, Ke et al. (2016) Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation. Epigenetics 11:819-830

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