Glial-neuronal interactions underlying the molecular feedback between HIV viral p

Summary

Principal Investigator: Sulie L Chang
Abstract: DESCRIPTION (provided by applicant): The long-term goal of this research is to delineate the possible mechanisms underlying the increased abuse of substances, such as methamphetamine (METH), by individuals who are human immunodeficiency virus-1 (HIV)-positive. In this two-year exploratory project, we propose to specifically examine the synergistic effects of methamphetamine (METH), an addictive psychostimulant, and HIV-1 viral proteins on glial-neuronal induction of inflammation in the rat brain. In the central nervous system (CNS), the glial cells are infected by the HIV-1 virus, causing neuroinflammation. Increased inflammation in the brain has been correlated with neurodegenerative diseases and behavioral disorders, such as HIV-1 induced neurodegeneration (HAND) and HIV-1 induced dementia (HAD). Moreover, METH abuse in the HIV-infected individual can lead to increased viral loads and severe brain-related disorders. For these studies, we will use both the non-infectious HIV-1 transgenic (HIV-1Tg) rat and primary cell culture models. The HIV-1Tg rat carries a gag/pol deleted provirus gene, and expresses 7 out of 9 HIV-1 viral proteins. This HIV-1Tg rat develops clinical manifestations of human HIV disease, and, thus, mimics the infection that results from the persistent presence of HIV-1 proteins in HIV patients given anti-retroviral therapy. Recently, using PCR array analysis, we showed that the pro- inflammatory cytokine, IL-1[unreadable], as well as the Ccl2, Ccl3, and Ccl7 chemokines, are increased to a greater extent in the brain of the HIV-1Tg rat compared to the F344 control rat. We have also demonstrated that there is elevated dopamine D1 receptor (D1R) expression in the prefrontal cortex of HIV-1Tg rats, and that these animals have greater METH-induced behavioral sensitization, as assessed by stereotypical head movement. Based on the literature and our previous data, we hypothesize that the abuse of substances, such as METH, in the presence of HIV-1 viral proteins, enhances glial activation, which affects neurons, and increases the activity of the dopaminergic system, thereby increasing the intake of METH. To test this hypothesis, we will first examine the glial-neuronal cell interaction in the brain of the HIV-1Tg rat with and without exposure to METH using immunohistochemistry. We will then identify gene expression changes in neurotransmitter activity, in particular, the dopaminergic system, as well as neuroinflammation-related markers. We will also isolate primary glial and neuronal cells from HIV-1Tg rats and examine gene expression changes in the dopaminergic and other neurotransmitter pathways, as well as inflammation, and apoptotic and oxidative stress markers after in vitro exposure to METH. Our specific aims include: 1) To determine the effects of METH and HIV viral proteins on glial and neuronal activation, neuroinflammation, and neurotransmitter modulation in the brain of the HIV-1Tg rat, and 2) To determine the effects of METH and HIV viral proteins on glial and neuronal activation, neuroinflammation, and neurotransmitter modulation in an ex vivo model using primary glial and neuronal cells isolated from the HIV- 1Tg rat brain To our knowledge, this proposal represents the first project to explore the effects of METH on glial-neuronal interactions and the subsequent effects on the dopaminergic system using the HIV-1Tg rat and primary cell cultures isolated from the HIV-1Tg rat. The data from this research will shed light on possible cellular and molecular mechanisms underlying the increased abuse of substances such as METH by HIV-positive individuals, and help to elucidate the glial-neuronal interactions associated with METH abuse and neuroAIDS. Our exploratory studies can also lead to better treatment approaches that will ultimately benefit both HIV-1 patients and substances abusers. Thus, the proposed studies have high clinical relevance and will contribute significantly to the understanding and treatment of neurological complications associated with substance abuse, HIV infection, and AIDS.
Funding Period: 2013-09-15 - 2015-08-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. CNS &Peripheral Viral Reservoirs/SIV Model of HIV HAART
    Janice E Clements; Fiscal Year: 2013
    ..We will also test eradication strategies designed to eliminate these reservoirs. ..
  2. CDART - Center for Drug Abuse Research Translation
    Michael T Bardo; Fiscal Year: 2013
    ..The long-range goal is to improve the design and implementation of targeted anti-drug preventive interventions. ..
  3. PRESYNAPTIC MECHANISMS OF NEURAL PLASTICITY
    Robert H Edwards; Fiscal Year: 2013
    ..and action of dopamine in the reward pathway: 1) The mechanism of dendritic dopamine release (Projects 1 and 3);2) The mechanism and physiological role of glutamate co-release by dopamine neurons (Project 3);3) Trafficking and regulation ..
  4. UMB Center for Pain Studies
    Susan G Dorsey; Fiscal Year: 2013
    ..abstract_text> ..
  5. Structure-function based development of JC virion specific antagonists for PML
    Walter Atwood; Fiscal Year: 2013
    ..The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application. ..
  6. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  7. CXCL8-mediated glial cross-talk and neuroprotection in HIV-1 Dementia
    Anuja Ghorpade; Fiscal Year: 2013
    ..abstract_text> ..
  8. Enduring Effects of Early-Life Serotonin Signaling
    Randy D Blakely; Fiscal Year: 2013
    ..abstract_text> ..
  9. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
    ..abstract_text> ..
  10. Effects of ethanol concentration in binge drinking during HIV-1 infection
    Sraboni Sarkar; Fiscal Year: 2013
    ....
  11. Effects of HIV- and ARV-Induced Oxidative Stress on Neuroglial Cells
    BRIGID JENSEN; Fiscal Year: 2013
    ..Translation of findings to an in vivo setting will provide a novel endogenous therapeutic avenue to potentially lessen severity or speed of progression of neurodegenerative diseases displaying evidence of oxidative stress. ..
  12. HIV Tropism, Persistence, Inflammation and Neurocognition in Therapy Initiation
    RONALD I SWANSTROM; Fiscal Year: 2013
    ..Collectively, these studies will bring a detailed understanding of viral replication and viral evolution, with the attendant issues of inflammation and neuronal damage, ..
  13. Neuron-Glia Mechanisms &Interactions Underlying Opioid Abuse-HIV-1 Comorbidity
    Kurt F Hauser; Fiscal Year: 2013
    ..He was recruited to VCU by the Dept. of Pharmacology and Toxicology to pursue these goals and receives tremendous support for this endeavor. ..
  14. Opioid Abuse, opportunistic infection and NeuroAIDS
    Sabita Roy; Fiscal Year: 2013
    ..pneumonia infection to potentiate and exacerbate neuronal damage. We propose to determine the mechanisms by which morphine contributes to neuronal dysfunction in HIV-infected individuals. ..
  15. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  16. GFAP as a novel HIV/neuroAIDS biomarker
    Johnny J He; Fiscal Year: 2013
    ....
  17. HIV NEUROBEHAVIORAL RESEARCH CENTER
    ROBERT KERNACHAN HEATON; Fiscal Year: 2013
    ..With these structures and processes the HNRC will continue to foster its national and international leadership role in neuro-HIV research, training, and treatment. ..
  18. Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
    PETER JESSE GASKILL; Fiscal Year: 2013
    ..abstract_text> ..
  19. Mechanisms and Interventions for Methamphetamine and HIV-1 Induced CNS Injury
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  20. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  21. CNS injury caused by HIV-1 and alcohol: Protective effects of CB2 activation
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  22. Glial versus Neuronal Caspase-3 in Opioid-HIV gp120 Neurotoxicity
    KIMBERLY LYNNE SAMANO; Fiscal Year: 2013
    ..With this information, a better understanding of underlying mechanisms are made possible which lead to new options in therapeutics, which have ramifications for opioid abusers and users infected with HIV-1. ..
  23. Stimulant Pharmacotherapy: Noradrenergic Targets
    THOMAS RICHARD KOSTEN; Fiscal Year: 2013
    ..5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations. ..
  24. Translational Methamphetamine AIDS Research Center (TMARC)
    Igor Grant; Fiscal Year: 2013
    ..TMARC's ultimate vision is to become a national resource for translational multidisciplinary research and training in the neuropathogenesis of HIV and substance use. ..
  25. Aptamer Imaging: A Theranostic Approach to Treat Substance Abuse
    Philip K Liu; Fiscal Year: 2013
    ..Because transcription factor binding domains are conserved from rodents to humans, our innovative technique, once validated, has potential for theranostic application, from rodents to primates. ..
  26. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..