Alcohol abuse is considered to be a ma or risk factor in the development of HIV-associated dementia. In addition, impaired function of the brain vasculature and disruption of the blood-brain barrier (BBB) might be critical factors in mechanisms of HIV-1 virus trafficking in the central nervous system (CNS). Evidence indicates that both alcohol and the viral gene product, the protein Tat, can induce injury or dysfunction of brain microvascular endothelial cells (BMEC), which can lead to the breakdown of the BBB. In the present grant application, we hypothesize that ethanol and Tat can cross-amplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus, combined exposure to ethanol and Tat can lead to accelerated entry of the HIV-1 into the CNS. This hypothesis is strongly supported by our preliminary data, which suggest that exposure to both Tat and ethanol can markedly induce oxidative stress in BMEC. In addition, we demonstrated that induction of cellular oxidative stress can lead to decreased expression of specific transmembrane proteins, such as occludin, which build intercellular junctions, i.e., the structures responsible for the integrity of the brain endothelium and functional BBB. Based on these facts, we developed the leading hypothesis of the current proposal that combined exposure to ethanol and Tat can exacerbate the disruption of the integrity of the cerebral vascular endothelium through the induction of cellular oxidative stress and the subsequent alterations of junctional protein expression. This hypothesis will be studied using in vitro and in vivo experimental settings. In our animal studies, we will employ both acute and chronic models of alcohol exposure, combined with Tat treatment. The long term goals of the current proposal are to determine mechanisms which may prevent ethanol and Tat-induced injury to BMEC. Thus, data arising from this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV-1 infection associated with alcohol abuse. We believe that a better knowledge of these processes will contribute to the possible development of therapeutic interventions to prevent IFIV- I entry into the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA013843-03
Application #
6798677
Study Section
Special Emphasis Panel (ZAA1-CC (16))
Program Officer
Lucas, Diane
Project Start
2002-09-10
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$147,000
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Andras, Ibolya E; Deli, Maria A; Veszelka, Szilvia et al. (2007) The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J Cereb Blood Flow Metab 27:1431-43
Hayashi, Kentaro; Pu, Hong; Andras, Ibolya E et al. (2006) HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. J Cereb Blood Flow Metab 26:1052-65
Flora, Govinder; Pu, Hong; Hennig, Bernhard et al. (2006) Cyclooxygenase-2 is involved in HIV-1 Tat-induced inflammatory responses in the brain. Neuromolecular Med 8:337-52
Lee, Y W; Hirani, A A; Kyprianou, N et al. (2005) Human immunodeficiency virus-1 Tat protein up-regulates interleukin-6 and interleukin-8 expression in human breast cancer cells. Inflamm Res 54:380-9
Pu, Hong; Tian, Jing; Andras, Ibolya E et al. (2005) HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. J Cereb Blood Flow Metab 25:1325-35
Andras, Ibolya E; Pu, Hong; Tian, Jing et al. (2005) Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab 25:1159-70
Flora, Govinder; Pu, Hong; Lee, Yong Woo et al. (2005) Proinflammatory synergism of ethanol and HIV-1 Tat protein in brain tissue. Exp Neurol 191:2-12
Toborek, Michal; Lee, Yong Woo; Flora, Govinder et al. (2005) Mechanisms of the blood-brain barrier disruption in HIV-1 infection. Cell Mol Neurobiol 25:181-99
Lee, Yong Woo; Eum, Sung Yong; Nath, Avindra et al. (2004) Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells. Cardiovasc Res 63:139-48
Pu, Hong; Tian, Jing; Flora, Govinder et al. (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 24:224-37

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