TAT MEDIATED BRAIN ENDOTHELIAL CELL DYSFUNCTION

Project: Research project

Description

Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood. We hypothesize that the viral gene product, the protein Tat is, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS and thus BMEC can be directly exposed to high concentrations of this protein. The present research application is designed to study selective mechanistic events associated with Tat-induced toxicity to BMEC. Based on our preliminary data, this research proposal will focus on oxidative- type cellular injury and death. An increased oxidative stress may affect cellular metabolism by induction of inflammatory genes which are regulated by transcription factors, such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Therefore, our studies will be focused on these signaling mechanisms and inflammatory gene expression, such as selected adhesion molecules, chemokines and inflammatory cytokines. In addition, we hypothesize that Tat-mediated decrease in BMEC viability can be caused by disturbances of polyamine metabolism, caspase activation and apoptotic cell death. Therefore, studies on these metabolic pathways also will be a focus of this research application. The majority of the proposed research will be performed with cultures of BMEC. The long term goals of the current proposal are to determine fundamental mechanisms of Tat- induced injury to BMEC. Thus, data arising from this proposal will be critical for a better understanding of vasculature alterations during the pathogenesis of HIV-associated dementia and for the possible development of therapeutic interventions.
StatusFinished
Effective start/end date4/1/009/1/10

Funding

  • National Institutes of Health: $266,666.00
  • National Institutes of Health: $265,301.00
  • National Institutes of Health: $286,406.00
  • National Institutes of Health: $264,700.00
  • National Institutes of Health: $253,400.00
  • National Institutes of Health: $290,250.00
  • National Institutes of Health: $253,400.00
  • National Institutes of Health: $44,558.00
  • National Institutes of Health: $253,400.00
  • National Institutes of Health: $72,500.00
  • National Institutes of Health: $265,994.00
  • National Institutes of Health: $275,373.00
  • National Institutes of Health: $50,000.00

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Endothelial Cells
Brain
Blood-Brain Barrier
Brain Injuries
Viral Proteins
AIDS Dementia Complex
Research
HIV
HIV-1
Peroxisome Proliferator-Activated Receptors
HIV Infections
Wounds and Injuries
Research Design
Oxidation-Reduction
Endothelium
Transcription Factor AP-1
Polyamines
Caspases
Metabolic Networks and Pathways
Chemokines

ASJC

  • Medicine(all)
  • Neuroscience(all)