Cocaine is a significant risk factor for contracting HIV-1 infection and subsequently developing AIDS. The proposed research is aimed to dissect the role of cocaine and HIV-associated epigenetic mechanisms in the development of HIV-associated neurocognitive disorders (HAND). In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drug addiction and also in development of neurodegenerative disorders. In the current study, we will focus on HDAC2 since it is known to play a critical role in cognitive function by regulating the density of dendritic spines and influencing synaptic transmission in mature neurons. However, the role of HDAC2 in development of HAND is not elucidated yet in the context of cocaine. In our published and preliminary studies, we found that HIV-1 Tat protein and HIV-1 infection upregulate HDAC2 expression with concomitant downregulation of CREB and CamKIIa and 17 other genes that are known to regulate synaptic plasticity. Further we have shown for the first time that cocaine significantly upregulated HDAC2 gene expression and downregulated miR-155 and transfection with miR-155 significantly inhibited HIV infection. Accordingly, we hypothesize that cocaine acts a co-factor in neuropathogenesis of HIV infection by modulating HDAC2 expression in CNS cells leading to transcriptional repression of genes that regulate neuronal activity and synaptic plasticity. The specific goals are to determine: 1) whether cocaine in association with HIV-1 virus modulates HDAC2 which in turn negatively regulates synaptic plasticity/ memory genes in primary human microglia, hippocampal neurons and astrocytes thereby contributing to the progression of HAND;2) whether inhibition of HDAC2 reverses the effects of cocaine and HIV-1 virus on neuronal plasticity genes and dendritic spine density and 3) can delivery of HDAC2 specific siRNA and miR-155 across the in vitro blood-brain barrier (BBB) model and in HIV-E SCID cocaine mouse model using transferrin coupled liposomal nanoformulation be explored as a therapeutic strategy for HAND. Thus, an understanding of cocaine and HIV-associated epigenetic changes and its implications in neuropathogenesis will have translational significance for therapeutic targeting and control of HAND in HIV-infected cocaine users.

Public Health Relevance

The proposed research will elucidate the cocaine and HIV-associated epigenetic mechanisms in the development of HIV-associated neurocognitive disorders (HAND). Further, we will also evaluate the efficacy of transferrin coupled liposomal nanoformulation to transmigrate across an in vitro blood-brain barrier (BBB) model as well as in the HIV-E SCID cocaine mouse model. These studies will have translational significance for therapeutic targeting and control of HAND in cocaine abusing HIV-infected patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA034547-01
Application #
8410634
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Satterlee, John S
Project Start
2013-03-01
Project End
2017-12-31
Budget Start
2013-03-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$363,559
Indirect Cost
$110,872
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Stewart, Tiffanie S; Nagesetti, Abhignyan; Guduru, Rakesh et al. (2018) Magnetoelectric nanoparticles for delivery of antitumor peptides into glioblastoma cells by magnetic fields. Nanomedicine (Lond) 13:423-438
Vashist, Arti; Kaushik, Ajeet; Vashist, Atul et al. (2018) Nanogels as potential drug nanocarriers for CNS drug delivery. Drug Discov Today 23:1436-1443
Parira, Tiyash; Figueroa, Gloria; Granado, Sherly et al. (2018) Trichostatin A Shows Transient Protection from Chronic Alcohol-Induced Reactive Oxygen Species (ROS) Production in Human Monocyte-Derived Dendritic Cells. J Alcohol Drug Depend 6:
Sagar, Vidya; Nair, Madhavan (2018) Near-infrared biophotonics-based nanodrug release systems and their potential application for neuro-disorders. Expert Opin Drug Deliv 15:137-152
Vashist, Arti; Kaushik, Ajeet; Vashist, Atul et al. (2018) Advances in Carbon Nanotubes-Hydrogel Hybrids in Nanomedicine for Therapeutics. Adv Healthc Mater 7:e1701213
Kaushik, Ajeet; Jayant, Rahul Dev; Bhardwaj, Vinay et al. (2018) Personalized nanomedicine for CNS diseases. Drug Discov Today 23:1007-1015
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
Tomitaka, Asahi; Arami, Hamed; Raymond, Andrea et al. (2017) Development of magneto-plasmonic nanoparticles for multimodal image-guided therapy to the brain. Nanoscale 9:764-773
Huang, Zaohua; Nair, Madahavan (2017) A CRISPR/Cas9 guidance RNA screen platform for HIV provirus disruption and HIV/AIDS gene therapy in astrocytes. Sci Rep 7:5955
Kaushik, Ajeet; Tiwari, Sneham; Jayant, Rahul D et al. (2017) Electrochemical Biosensors for Early Stage Zika Diagnostics. Trends Biotechnol 35:308-317

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