Studies of the pathogenesis of atherosclerotic lesions have been guided by several hypotheses: the cholesterol hypothesis has been central for many years and has provided fruitful However, there has developed appreciation of the fact that the process involves more than lipid deposition and that vascular injury may be caused by various agents such as oxidized lipids, viruses, oxygen free radicals and substances other than lipids may gain access to vessel walls via the blood. It has become evident that the various injurious agents invoke a large interconnected network of factors responsible for defending against a wide range of different insults. Moreover, for survival of an organism the responses evoked by various forms of injury must maintain a balance between destroying or removing a noxious entity and limiting the destructive effects of this part of the defense system. The main peptide in the amyloid substance of """"""""reactive' type of amyloid derive from circulating precursors, serum amyloid A proteins secreted by the liver and associated with HDL lipoproteins, i.e. as apoSAAs. Furthermore they are produced locally by a variety of cells including those of the type involved in development of atherosclerotic plaque such as endothelial cells, vascular smooth muscle, and macrophages. Several functions seem to be emerging for products of this ancient family of genes including sequestration of lipid-soluble toxins, redirection of HDL cholesterol transport, interference with platelet aggregation and inhibition of leukocyte functions. We propose to examine, using in vivo and in vitro experiments, the potential modulator activities of the apoSAAs in relation to local reactions to injurious agents such as may be driving development of lesions of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040079-08
Application #
2028366
Study Section
Pathology A Study Section (PTHA)
Project Start
1988-03-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1998-11-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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