Atherosclerosis and its complications, including plaque rupture, are the major cause of morbidity and mortality in the United States. There is abundant pathological, epidemiological and experimental evidence linking atherosclerosis and inflammation. Additional pathological and experimental evidence suggests that apoptosis of vascular cells contributes to atherosclerotic lesion progression and plaque rupture. However, there is, as yet, no direct experimental evidence demonstrating that endothelial cell activation or apoptosis is prerequisite for atherosclerotic lesion formation and progression or for plaque rupture. The central hypothesis of this proposal is that endothelial cell activation and apoptosis are important events in atherogenesis. The goal of this proposal is to investigate the signaling pathways involved in endothelial cell activation and apoptosis in both in vitro and in vivo models. We will focus on FADD (Fas-associated death domain-containing protein), which we have shown is involved in the regulation ofNF-v,kB, a key transcription factor controlling inflammatory responses, as well as in signaling for apoptosis. To accomplish this goal we propose the following Specific Aims: 1) to define the role of FADD in the regulation of NF-kB activation; 2) to identify components of the FADD complex involved in regulation of NF-,kB; 3) to determine the effect of blockade of endothelial activation and apoptosis in acute inflammatory responses using inducible, endothelial-restricted transgenes that inhibit NF-vd3 activation or block caspases; and 4) to determine the role of endothelial cell activation and apoptosis in atherosclerotic lesion formation using the transgenic mice generated and characterized in Aim 3 crossed with ApoE-/-.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL072262-01
Application #
6678758
Study Section
Special Emphasis Panel (ZHL1-PPG-N (O2))
Project Start
2002-09-30
Project End
2007-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$405,192
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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