Abstract

Mononuclear leukocyte adherence to endothelium is a pivotal event in the inflammatory phase of arterial diseases such as atherosclerosis. The current model of leukocyte emigration predicts that leukocytes first adhere transiently via selectin receptors with subsequent firm adherence mediated by integrin receptors, triggered to a high avidity state by local stimuli. This proposal will examine the regulation of leukocyte adhesion, focusing on the role of selectin receptors in monocyte emigration in the arterial circulation and the regulation of beta1 integrin affinity. The following Specific Aims are proposed: 1) to determine the role of selectins in mononuclear phagocyte emigration into the arterial wall of rabbits following stimulation with chemotactic agents; 2) to determine the effect of affinity modulation by the activating beta1 MAb 8A2 in vivo; 3) to determine the adhesion pathway involved in beta1 MAb 4B5-stimulated leukocyte adherence to endothelium; 4) to examine mechanisms of high affinity mononuclear leukocyte adhesion; and 5) to determine the cytoskeletal associations of high affinity beta1 receptors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018645-25
Application #
6202176
Study Section
Project Start
1999-09-30
Project End
2000-09-29
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
25
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

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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