Fellowship for Wen Huang: Novel Mechanisms of PPAR-mediated Protection Against HIV-1 Mediated Disruption of Endothelial Intergrity

  • Toborek, Michal (PI)
  • Huang, Wen (CoI)

Grants and Contracts Details


Tight junctions (TJs) are the main structural and functional elements that regulate the blood-brain barrier (BBB) integrity. Our preliminary data indicated that exposure of human brain microvascular endothelial cells (HBMEC) to human immunodeficiency virus-1 (HIV-1) resulted in a decreased expression of TJs. Interestingly, overexpression of peroxisome proliferator-activated receptor (PPAR)- and  or exposure to PPAR agonists attenuated HIV-1 mediated dysregulation of TJs partly by inhibition of matrix metalloproteinase (MMP) activity. However, the mechanisms of downregulation of MMP activity by PPARs in the protection of BBB are not fully understood. MMP expression is regulated by transcription factors and MMPs are closely associated with caveolae and co-localize with caveolin proteins on the surface of endothelial cells. The main hypothesis of the current porposal is that PPARs protect against HIV-induced MMP overexpression by attenuating cellular oxidative stress and downregulation of redox-regulated transcription. In Aim 1, we will study the hypothesis that PPARα and PPARγ, acting through caveolae-associated Ras signaling, inhibit MMP-2 and MMP-9 promoter activity and thus protect against HIV-induced disruption of tight junction integrity. In Aim 2, we will evaluate the role of specific HIV-1 proteins and the protective effects of PPARs in MMP-2 and MM-9-mediated alterations of TJs protein expression and disruption of the BBB integrity. The proposed studies will contribute to better knowledge on the mechanisms of the regulation of MMP expression by PPARs in the protection of HIV-induced BBB dysfunction. In broader aspect, data generated in this proposal are likely to provide additional information on the therapeutic potential of PPAR agonists in endothelial injury caused by inflammatory and/or vascular diseases.
Effective start/end date7/1/096/30/11


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