Impaired function of the brain vasculature might be a critical factor in mechanisms of HIV-1 virus trafficking in the central nervous system (CNS). We hypothesize that the viral gene product, the protein Tat, at least in part, is responsible for this effect. We have evidence that exposure to Tat can induce activation and injury to brain microvascular endothelial cells (BMEC) with subsequent breakdown of the blood-brain barrier (BBB). Disrupted BBB may allow accelerated entry of the HIV-1 into the CNS. In addition, Tat-induced activation of BMEC can lead to upregulation of adhesion molecules and inflammatory cytokines and thus facilitate adherence of infected monocytes to the brain endothelium and their migration to underlying tissues. Our preliminary data indicate that Tat is a strong inducer of the tumor necrosis factor-alpha (TNF) gene in BMEC. TNF is one of the most potent inducers of inflammatory responses in endothelial cells. Based on these facts, we developed a leading hypothesis of the current proposal that endogenous production of TNF can induce oxidative stress and markedly enhance Tat-mediated injury to BMEC. In support of this hypothesis, we demonstrated that neutralization of endogenous TNF produced by BMEC can markedly protect against Tat-induced endothelial injury. The present research application is designed to study the effects of BMEC endogenous TNF on oxidative-type cellular injury. We hypothesize that Tat-induced endogenous TNF can exacerbate cellular oxidative stress and inflammatory responses of BMEC induced by Tat. These hypotheses will be studied using both in vitro and in vivo experimental settings. The long term goals of the current proposal are to determine mechanisms which may prevent Tat- induced injury to BMEC. Thus, data arising from this proposal will be critical for a better understanding of disruption of the BBB during HIV-1 infection and for the possible development of therapeutic interventions to prevent HIV-1 entry into the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063022-04
Application #
6760892
Study Section
Special Emphasis Panel (ZRG1-AARR-6 (01))
Program Officer
Joseph, Jeymohan
Project Start
2001-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$253,400
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Leda, Ana R; Dygert, Levy; Bertrand, Luc et al. (2017) Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS via the Internal Carotid Artery. J Vis Exp :
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2017) Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J Vis Exp :
András, Ibolya E; Leda, Ana; Contreras, Marta Garcia et al. (2017) Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79:12-22
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2016) Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity. Sci Rep 6:39738
Park, Minseon; Levine, Harry; Toborek, Michal (2016) Exercise protects against methamphetamine-induced aberrant neurogenesis. Sci Rep 6:34111
Castro, Victor; Bertrand, Luc; Luethen, Mareen et al. (2016) Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. FASEB J 30:1234-46
András, Ibolya E; Toborek, Michal (2016) Extracellular vesicles of the blood-brain barrier. Tissue Barriers 4:e1131804
Eum, Sung Yong; Jaraki, Dima; András, Ibolya E et al. (2015) Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 287:258-66
Bertrand, Luc; Toborek, Michal (2015) Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz. Mol Pharmacol 88:304-15
Równicka-Zubik, Joanna; Su?kowski, Leszek; Toborek, Michal (2014) Interactions of PCBs with human serum albumin: in vitro spectroscopic study. Spectrochim Acta A Mol Biomol Spectrosc 124:632-7

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