Unlike necrosis, apoptosis is classically considered to be """"""""silent,"""""""" i.e., self-contained and non-inflammatory. We have developed a system for regulating apoptosis of smooth muscle cells (SMCs) in the rat carotid artery in vivo, and have used this system to determine that SMC apoptosis initiated by FADD over expression, or by Fas ligation, includes a specific program of expression of pro-inflammatory genes that results in recruitment of macrophages. In this application, we propose to further define this program of gene expression, determine the mechanism through which it is regulated, and further investigate the consequences of smooth muscle cell apoptosis in vivo. To do this, we propose the following specific aims:
SPECIFIC AIM 1 : Use tet-regulated expression of FADD in the rat carotid artery to determine the long-term consequences of SMC apoptosis in the neointima, including the clinically important processes of vascular remodeling, thrombosis, and plaque rupture.
SPECIFIC AIM 2. Determine whether the program of gene expression activated by Fas in human SMCs includes additional genes, whether it is cell-type specific, and how activation of expression of component genes reflect activation of specific signal transduction pathways.
SPECIFIC AIM 3. Determine the signal transduction pathway(s) through which Fas activation leads to transcript up regulation in human SMCs.
SPECIFiC AIM 4. Determine the mechanisms that regulate SMC resistance to Fas-induced apoptosis and that may promote SMC proliferation under some circumstances.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069066-03
Application #
6686420
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
2001-12-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$303,200
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195