Approximately one-third of HIV-1 infected individuals develop HIV-1-associated neurocognitive disorders (HAND). Symptoms range from minor difficulties to severe neurodegenerative dementia and even with the advent of highly active antiretroviral therapy (HAART), while severe HIV-associated dementia is less common, minor cognitive motor disorders remains an important part of infection. The deleterious effects of opiates are complex and information regarding the actions of drugs of abuse on glial cell function is very limited though they are known to be critical to opiate response. Moreover, the consequent effects of the actions of drugs of abuse and the manifestation of substance abuse on neuronal function are not well known. The proposed project will investigate the role of autophagy in microglia-induced neuroAIDS in the context of substance abuse. The three correlated specific aims are directed at: 1) identifying a novel mechanism in the biology of microglia that regulates HIV-1 replication and whether morphine converges on HIV-1 infection through this pathway~ 2) characterization at cellular levels the consequences of HIV-1 induced lysosomal dysfunction and whether prior and/ or concurrent substance abuse modifies cell function~ 3) examining the signaling pathways and the significance (protective vs. toxic) of the autophagy process activated by HIV-1 and morphine in microglia cells and neurons. Dr. El-Hage has the expertise, leadership, and motivation necessary to run a successful research program and the purpose of getting this award is to enable Dr. El-Hage to become an independent scientist.

Public Health Relevance

The goals of this proposal are twofold~ (i) to study the consequences underlying HIV-1 and morphine deregulation of autophagy on microglia cell function, and (b) to determine whether autophagy plays a protective role or instead contributes to pathogenic neuronal cell death exposed to HIV-1 and substance abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036154-04
Application #
8823758
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Wu, Da-Yu
Project Start
2014-08-10
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Ojha, Chet Raj; Rodriguez, Myosotys; Lapierre, Jessica et al. (2018) Complementary Mechanisms Potentially Involved in the Pathology of Zika Virus. Front Immunol 9:2340
Lapierre, Jessica; Rodriguez, Myosotys; Ojha, Chet Raj et al. (2018) Critical Role of Beclin1 in HIV Tat and Morphine-Induced Inflammation and Calcium Release in Glial Cells from Autophagy Deficient Mouse. J Neuroimmune Pharmacol :
Ojha, Chet Raj; Lapierre, Jessica; Rodriguez, Myosotys et al. (2017) Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications. Viruses 9:
Rodriguez, Myosotys; Lapierre, Jessica; Ojha, Chet Raj et al. (2017) Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes. Viruses 9:
Rodriguez, Myosotys; Kaushik, Ajeet; Lapierre, Jessica et al. (2017) Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood-Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro. J Neuroimmune Pharmacol 12:120-132
Rodriguez, Myosotys; Lapierre, Jessica; Ojha, Chet Raj et al. (2017) Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation. Sci Rep 7:1862
Kaushik, Ajeet; Jayant, Rahul D; Nikkhah-Moshaie, Roozbeh et al. (2016) Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Sci Rep 6:25309
Dever, Seth M; Rodriguez, Myosotys; El-Hage, Nazira (2016) ?-Adrenergic receptor gene expression in HIV-associated neurocognitive impairment and encephalitis: implications for MOR-1K subcellular localization. J Neurovirol 22:866-870
Dever, Seth M; Rodriguez, Myosotys; Lapierre, Jessica et al. (2015) Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 6:653
Xu, Ruqiang; El-Hage, Nazira; Dever, Seth M (2015) Fluorescently-labeled RNA packaging into HIV-1 particles: Direct examination of infectivity across central nervous system cell types. J Virol Methods 224:20-9

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