Alcohol abuse remains one of the major health problems with approximately 14 million Americans (<5% of total population) suffering from alcohol abuse. However, the prevalence of chronic alcohol consumption among HIV-positive individuals has been reported to be between 29 and 60% in US. In view of emerging results from several laboratories, it is becoming clear that alcohol abuse contributes to HIV replication, disease progression and development of HIV-associated dementia. Furthermore both alcohol and HIV are independently known to be neurotoxic, but it is not known with certainty whether they will have synergistic effect in alcohol addicted HIV-1 positive individuals and cause increased production of proinflammatory. This application is designed to address this gap in the existing knowledge. We will study the combined effect of the alcohol and 2 virotoxins (HIV-1 gp120 and Tat,) on cytokine as well chemokine production, markers of oxidative stress, apoptosis, PPAR-? in astrocytes/neurons, and whether these detrimental effects can be abrogated by use of the antagonists of alcohol metabolism, the virotoxin-specific siRNAs and PPAR-? agonists. These in vitro studies will be extended to in vivo situation where effect of chronic alcohol consumption will be studied in HIV-1 Tat and gp120 transgenic mice. These mice will be used for assessment of cytokine and chemokine expression, neuronal apoptosis in brain as well as leakage in the blood brain barrier and whether use of alcohol antagonist and PPAR-? agonists will abrogate the alcohol-mediated neurotoxicity.

Public Health Relevance

This application proposes to dissect mechanism of increased neuroinflammation in alcohol-dependent HIV-1-infected individuals. We will study the role of proinflammatory cytokines and chemokine and whether their over-expression in the CNS leads to increased neurotoxicity. We will also determine role of antagonist of alcohol metabolism, siRNA and PPAR-gamma agonists in the management of neuroinflammation. These in vitro results will be extended to an in vivo model system using transgenic mice.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AA020806-03
Application #
8692615
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Regunathan, Soundar
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Kansas City
State
MO
Country
United States
Zip Code
64110
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Wei, Ding; Li, Qian; Wang, Xi-Long et al. (2015) Oncolytic Newcastle disease virus expressing chimeric antibody enhanced anti-tumor efficacy in orthotopic hepatoma-bearing mice. J Exp Clin Cancer Res 34:153
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Li, Hai-Yan; Ju, Di; Zhang, Da-Wei et al. (2015) Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Sci Rep 5:16552
Liu, Xun; Kumar, Anil (2015) Differential signaling mechanism for HIV-1 Nef-mediated production of IL-6 and IL-8 in human astrocytes. Sci Rep 5:9867

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