Grants and Contracts Details
Description
Impaired function of the brain vasculature can contribute to HIV trafficking into the CNS and the
development of neurodegenerative changes associated with HIV infection. Indeed, activation or dysfunction
of brain microvascular endothelial cells (BMEC) can lead to the breakdown ofthe blood-brain barrier (BBB),
induction of inflammatory responses, and provide an entry route for the HIV into the CNS. The leading
hypothesis of our research is that the viral gene product, HIV Tat protein, can be responsible for
BMEC injury and impaired function of the BBB. Furthermore, we hypothesize that alterations of redox
balance may be the common denominator of Tat-induced activation and dysfunction ofBMEC. In support of
these hypotheses, we obtained strong evidence that Tat treatment can dramatically downregulate peroxisome
proliferator activated receptor (PPAR) activation and thus suppress physiological functions of these critical
anti-inflammatory nuclear receptors. This research proposal will focus on the consequences of Tat-induced
alterations of PPAR activation, namely, overexpression of proinflammatory genes, dysregulation of
junctional protein expression, and disturbances of endothelial barrier function. In addition, we
hypothesize that Tat-induced alterations of BMEC redox status can lead to up regulation of the efflux
transport systems on the brain endothelium and thus prevent an effective anti-HIV therapy in the
CNS. The proposed research combines elements of clinical approaches, such as disruption of the BBB and
the development of drug resistance, with molecular and vascular biology. It is based on the unique and
innovative co-cultures of human brain endothelial cells with astrocytic cell lines which produce Tat (the
SVGA-Tat cells). In addition, part of the project involves animal studies. The long-term goals of this
proposal are to determine the mechanisms responsible for Tat-induced injury to BMEC, disruption of the
BBB and HIV entry into the CNS. In a broader aspect, this proposal will contribute to better knowledge of
how injury to brain endothelium can contribute to the development ofneuroAIDS.
Status | Finished |
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Effective start/end date | 4/1/00 → 9/1/10 |
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