This is a study of human atherosclerotic tissue. We have shown that the cells characterizing such lesion result from a clonal expansion of smooth muscle cells existing in the intima. This study will address the mechanism of this clonal expansion by molecular biologic studies looking for the time course of clonality by characterizing on x-linked heteroallellic marker over the time course of lesion formation. Similarly we will use differential cloning methods to look for markers that distinguish these intimal cells and we will use cultured cells from human lesions to explore possible mechanisms of apoptotic selection. The overall objective of this proposal is to explore the properties that distinguish plaque smooth muscle cells from normal medial smooth muscle. This objective grows out of three simple facts: (1) the intima is defined by the properties of the intimal smooth muscle cell; (2) atherosclerosis is a focal disease of the arterial intima, and (3) the cells of the atherosclerotic lesion comprise a clone.
The Specific Aims are: (1) to determine the time course of monoclonality; (2) to determine whether clonal expansion occurs in vitro; (3) to define intimal-unique genes that mark the plaque smooth muscle cell; (4) to examine the relative role of cell death in expansion of the intima and loss of the media at sites of atherosclerotic progression; and (5) to look for mutations or genetic instability that could confer a proliferative or anti-apoptotic advantage on plaque smooth muscle cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058083-04
Application #
6537307
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$375,109
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Adams, Lawrence D; Geary, Randolph L; Li, Jing et al. (2006) Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap. Arterioscler Thromb Vasc Biol 26:319-25
Mulvihill, Eileen R; Jaeger, Jochen; Sengupta, Rimli et al. (2004) Atherosclerotic plaque smooth muscle cells have a distinct phenotype. Arterioscler Thromb Vasc Biol 24:1283-9
Schwartz, Stephen M; Bornfeldt, Karin E (2003) How does diabetes accelerate atherosclerotic plaque rupture and arterial occlusion? Front Biosci 8:s1371-83
Geary, Randolph L; Wong, James M; Rossini, Anthony et al. (2002) Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 22:2010-6
Adams, L D; Geary, R L; McManus, B et al. (2000) A comparison of aorta and vena cava medial message expression by cDNA array analysis identifies a set of 68 consistently differentially expressed genes, all in aortic media. Circ Res 87:623-31
Ikari, Y; McManus, B M; Kenyon, J et al. (1999) Neonatal intima formation in the human coronary artery. Arterioscler Thromb Vasc Biol 19:2036-40