Studies of human atherosclerotic plaques and animal models have established a central role for the macrophage in atherogenesis. Further, lesions that tend to rupture, and lead to the majority of clinical manifestations of atherosclerosis, are characteristically rich in macrophages and thus implicate the macrophage as a key regulator of plaque stability. Despite these observations, it is still unclear how the multiple pro- and anti-inflammatory capabilities of the macrophage are balanced within lesions. This interdisciplinary program will use a combination of approaches to probe the role of specific genes in the regulation of the macrophage inflammatory process in atherogenesis. Genes central to monocyte/macrophage trafficking into lesions and pathways regulating their activation and survival within lesions will be the focus of the program. In addition to mechanistic studies in cultured macrophages, all of the projects will specifically test the significance of these target genes in mouse models of atherosclerosis, with an emphasis on the examination of advanced lesions of atherosclerosis that characterize the clinically relevant human disease. Detailed analysis of the mouse lesions will be coordinated and standardized by the Mouse Atherosclerosis Core that will allow direct comparison of the different modulations of the inflammatory response within lesions. By asking whether perturbation of specific inflammatory genes is sufficient to accelerate or retard the progression of advanced lesions of atherosclerosis using identical protocols, this program has the potential to significantly advance our understanding inflammatory processes in atherogenesis and identify targets for intervention with cardiovascular disease progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018645-35
Application #
7739511
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Goldberg, Suzanne H
Project Start
1997-09-30
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
35
Fiscal Year
2010
Total Cost
$2,760,325
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kocarnik, Beverly M; Boyko, Edward J; Matsumoto, Alvin M et al. (2016) Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years. Obes Res Clin Pract 10:624-632
Nishizawa, Tomohiro; Kanter, Jenny E; Kramer, Farah et al. (2014) Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep 7:356-65
Wight, Thomas N; Kinsella, Michael G; Evanko, Stephen P et al. (2014) Versican and the regulation of cell phenotype in disease. Biochim Biophys Acta 1840:2441-51
Kang, Inkyung; Yoon, Dong Won; Braun, Kathleen R et al. (2014) Expression of versican V3 by arterial smooth muscle cells alters tumor growth factor ? (TGF?)-, epidermal growth factor (EGF)-, and nuclear factor ?B (NF?B)-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion. J Biol Chem 289:15393-404
Ruppert, S M; Hawn, T R; Arrigoni, A et al. (2014) Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res 58:186-92
Wight, Thomas N; Kang, Inkyung; Merrilees, Mervyn J (2014) Versican and the control of inflammation. Matrix Biol 35:152-61
Tsubota, Yoshiaki; Frey, Jeremy M; Tai, Phillip W L et al. (2013) Monocyte ADAM17 promotes diapedesis during transendothelial migration: identification of steps and substrates targeted by metalloproteinases. J Immunol 190:4236-44
Reed, May J; Damodarasamy, Mamatha; Chan, Christina K et al. (2013) Cleavage of hyaluronan is impaired in aged dermal wounds. Matrix Biol 32:45-51
Wilson, Carole L; Gough, Peter J; Chang, Cindy A et al. (2013) Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults. Mech Dev 130:272-89
Lund, Susan Amanda; Wilson, Carole L; Raines, Elaine W et al. (2013) Osteopontin mediates macrophage chemotaxis via ?4 and ?9 integrins and survival via the ?4 integrin. J Cell Biochem 114:1194-202

Showing the most recent 10 out of 631 publications