Opiate abuse and HIV-1 have been described as two linked global health crises, and despite the advent of anti-retroviral therapy, abuse of opiates has been shown to result in increased neurologic and cognitive deficits. Using the morphine-dependent rhesus macaques (RM) infected with CCR5-utilizing SIVR71/17E we recapitulated the human syndrome demonstrating augmentation of neuropathology &neuroinflammation and rapid disease progression compared with SIV-infected controls. Mortality in these rapid progressors was associated with robust viral replication in both the periphery &the brain. MicroRNA (miR)-mediated regulation of disease pathogenesis represents an evolving area of research that has ramifications for identification of potential therapeutic targets for various neurodegenerative disorders for which currently there exists no cure. Based on the similarities between the chronology of lentiviral infection in humans and macaques, the SIV/RM model offers a unique platform to perform controlled studies on the role of morphine in potentiating disease pathogenesis. The goal of the present application is to address how interactions between morphine &SIV in the acute phase of infection impact disease outcome in the chronic stage in the context of miR-mediated regulation of neurotoxicity. The innovative aspects of this proposal are based on our unique observation that in chronically (SIV)-infected RMs, morphine mediated potentiation of neuropathogenesis correlates with dysregulation of miRs, with specific upregulation of miR-29b (that is also upregulated in Alzheimer's &Parkinsons diseases) in both the peripheral blood mononuclear cells (PBMCs) as well as post mortem brain tissue. The hypotheses to be tested are that: a) morphine-mediated potentiation of SIV neuropathogenesis involves, in part, upregulation of miR-29b during the early (acute phase) of infection and, b) based on target identification using computer algorithms upregulation of miR-29b is critical for regulating genes controlling neuronal survival such as the platelet-derive growth factor (PDGF) and its receptor (PDGF-R) dyad.
Specific Aim 1 will be aimed at tracking morphine-mediated dysregulation of miR profiles (with emphasis on miR-29b) in the periphery &CNS of SIV-infected macaques during acute (14d pi) infection. These will be compared miR data obtained from the historical archived tissues of chronically infected RMs [ongoing parent study].
Specific Aim 2 will test the hypothesis that morphine-induced alteration in miR-29b targets the expression of neurotropic factors such as platelet-derived growth factor (PDGF) and its receptor, culminating into increased neuronal apoptosis.

Public Health Relevance

Drug abuse among HIV-infected patients poses a major challenge for health care management and one of the hallmark features of opiate abuse is increased neuronal toxicity in the setting of HIV infection. In the proposed project, we will use a established opiate dependent simian model of neuroAIDs combined with microRNA profiling to understand how periphery-CNS cross talk leads to disease progression. These findings could have ramifications for future development of miR-29b as a biomarker for HIV-associated neuronal toxicity in opiate abusers.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DA035203-02
Application #
8606207
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Liao, Ke; Guo, Minglei; Niu, Fang et al. (2016) Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis. J Neuroinflammation 13:33
Marcario, Joanne K; Pendyala, Gurudutt; Riazi, Mariam et al. (2016) Effects of Morphine on Behavioral Task Performance in SIV-Infected Rhesus Macaques. J Neuroimmune Pharmacol 11:348-57
Cai, Yu; Arikkath, Jyothi; Yang, Lu et al. (2016) Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy 12:225-44
Yang, Lu; Chen, Xufeng; Simet, Samantha M et al. (2016) Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage. Am J Respir Cell Mol Biol 55:736-748
Cai, Yu; Yang, Lu; Hu, Guoku et al. (2016) Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy. J Cell Biol 215:245-258
Niu, Fang; Yao, Honghong; Liao, Ke et al. (2015) HIV Tat 101-mediated loss of pericytes at the blood-brain barrier involves PDGF-BB. Ther Targets Neurol Dis 2:
Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy et al. (2015) Cocaine-mediated microglial activation involves the ER stress-autophagy axis. Autophagy 11:995-1009
Yao, Honghong; Bethel-Brown, Crystal; Niu, Fang et al. (2014) Yin and Yang of PDGF-mediated signaling pathway in the context of HIV infection and drug abuse. J Neuroimmune Pharmacol 9:161-7
Niu, Fang; Yao, Honghong; Zhang, Wenting et al. (2014) Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders. J Neurosci 34:11812-25
Buch, Shilpa (2014) Growth factor signaling: implications for disease & therapeutics. J Neuroimmune Pharmacol 9:65-8

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