This is a proposal to explore in depth the biology of the artery wall in relation to the etiology and pathogenesis of atherosclerosis. This program studies endothelium, smooth muscle monocytes/macrophages, T cells, and platelets and their interrelationships in arterial biology anci atherogenesis, with particular emphasis on 1) understanding the growth factors, including platelet-derived growth factor (pDGF), derived from platelets, macrophages, endothelium, and smooth muscle in terms of the mechanisms by which they induce mitogenesis and chemotaxis and alter cell functions, such as adhesive interactions; 2) in vivo studies of atherogenesis and restenosis postangioplasty in hypercholesterolemic nonhuman primates and rabbits, and atherogenesis in transgenic mice; 3) the role of matrix metalloproteinases and heparin in the regulation of smooth muscle function in vitro and in vivo; 4) the role of a relatively recently discovered molecule, osteopontin, in its capacity as an adhesive molecule and as a stimulus for smooth muscle migration; 5) the adhesive interactions between leukocytes and endothelium and of smooth muscle in the processes of atherogenesis and inflammation; 6) factors that modulate and determine the nature of cholesterol and lipid trafficking in cells and the roles of these processes in intracellular cholesterol homeostasis and atherogenesis; 7) the role of proteoglycans in influencing proliferation, migration, and adhesive events in the genesis of the atherosclerotic plaque; 8) the regulation of vascular cell function by thrombospondins and SPARC and their roles in growth factor retention and modulation of cell/matrix interactions; 9) regulation of smooth muscle function by tyrosine phosphatases; and 10) studies to characterize intracellular signal transduction mechanisms activated by fluid flow over endothelial cells. All of these projects are interactive and relate to further testing and analysis of the Response-to-Injury Hypothesis of Atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018645-25
Application #
6078028
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
1985-09-30
Project End
2000-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
25
Fiscal Year
1999
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
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
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 7:356-365
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
Cieslewicz, Maryelise; Tang, Jingjing; Yu, Jonathan L et al. (2013) Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. Proc Natl Acad Sci U S A 110:15919-24
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

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