HIV-Induced Dopamnergic Changes and Methamphetamine Toxicity Mediated through Mic

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DESCRIPTION (provided by applicant): This is a pilot project in response to PAR-10-021 in the broad area of drug abuse research in HIV/AIDS. The goal of the project is to understand how HIV-infected macrophages combine with methamphetamine (Meth) to cause alterations in dopaminergic neural cells and determine whether targeting a microRN (miR) can reverse or prevent dysfunction. Drugs of abuse, such as methamphetamine and cocaine, are chemically similar to dopamine and cause dopaminergic dysfunction in the brain by reversing the dopamine transporter and thus activating dopamine receptors and cause accumulation of high concentrations of dopamine in the synaptic space. Further, methamphetamine causes malfunction of the vesicular monamine transporter in dopaminergic neurons, leading to dysfunctional packaging of vesicular dopamine, accumulation of dopamine in the cytoplasm and downstream oxidative stress. It is also known that HIV and viral infection in the brain lead to dopaminergic cell loss in the long-term infected brain, though the mechanism is not well understood. Drug abuse and drug addiction in the HIV-infected population pose significant public health risks and new knowledge on the basic biochemical mechanisms behind drugs of abuse and the etiology and pathogenesis of HIV/AIDS. Based on investigator-generated data, we hypothesize that that Meth and HIV combine to induce changes in miR of DA neurons, specifically miR-9, miR-124, miR-125a, miR-130b, and let-7d; with co- occurring detriments to DA synthesis, metabolism, and transport and these effects can be prevented or reversed by augmenting specific miRs. Centered on this hypothesis, we aim to: 1. Understand the combined effects of Meth and HIV on miR expression, DA synthesis, metabolism, and transport; and 2. Intervene to prevent dopaminergic deficits caused by HIV and Meth by exogenously altering miR function. Our model of study will be cell culture: SH-SY5Y cells and HIV-infected monocytes. Our approach is to use loss-of-function and gain-of-function techniques. By overexpressing or inhibiting specific miRs and measuring dopamine metabolites, transporters, and enzymes, we can understand how miR mediates dopaminergic dysfunction caused by HIV. This project aims to improve HIV treatment and outcomes in drug abusers through a better understanding of the interactions with drugs of abuse and HIV/AIDS disease process. Results from this project will further our understanding of the gene- (regulation through miR) and environment- (HIV-infection) influence risk and protective factors of drug abuse. Knowledge will be applied to help design therapies to reverse or prevent chemical addiction in HIV/AIDS. Results from this project will be leveraged for future research on in understanding the role of miRs in drugs of abuse and HIV/AIDS and medications used to treat HIV. Futures studies also include studying the role of miRs in HIV/AIDS and underlying neurobiology of drug abuse and addiction. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse and human immunodeficiency virus (HIV) infection represent significant public health risks that combine to produce a "double epidemic." This project seeks to understand the molecular genetic intersection and neurochemical changes that occur when neurons are exposed to the two insults. Results from this study would provide a deeper understanding of the molecular mechanisms of neurochemical changes in HIV and methamphetamine abuse and provide possible therapeutic interventions to treat the etiology and neuropathogenesis of HIV in the drug-abusing population.