Grants and Contracts Details
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.
|Effective start/end date
|8/1/01 → 7/31/06
- National Institute of Mental Health: $1,293,643.00
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