We propose to examine cellular mechanisms in atherogenesis, emphasizing the role of cell surface charge in the uptake of plasma proteins, the influence of hemodynamic shear strees in the initiation, augmentation and localization of atherosclerosis, monocyte-lipoprotein interactions with reference to arterial cellular lipid accumulation, lipase activity and SMC proliferation, factor influencing monocyte-macrophase recruitment to the arterial wall, and finally, the biosynthesis and regulation of lipoprotein lipase, an important enzyme in the catabolism of traiglyceride-rich lipoproteins. In PROJECT A the influence of cationic ligands including cationized ferritin and PDGF on receptor-mediated, adsorptive and bulk phase endocytosis will be studied, with reference both to ligand charge and charge density, enzymatic modifications to cell surface associated anionic proteins, and the function of the cytoskeleton. PROJECT B will study endothelial responses to hemodynamic shear stress in vitro using a direct visualization parellel plate channel flow viscometer, and in vivo using models of aortic coarctation and bypass, with emphasis on cellular denudation, geometry, orientation, endocytosis, substrate and membrane lipid composition. PROJECT C examines the influence of monocyte activiation on lipoprotein binding, internalization, and lipid accumulation, the production of lipoprotein lipase, alterations to lipoprotein structure and composition, and on monocyte production of SMC mitogen. PROJECT D will examine arterial monocyte-macrophage recruitment with reference to monocyte-cellular attachment, the influence of lipid augmentation or depletion on monocyte-cellular attachment, the influence of lipid augmentation or depletion on monocyte chemotaxis, the production and characterization of arterial SMC-derived chemo-attractant activity, and the evolution, identification, and quantitation of monocyte derived macrophages in vascular and non-vascular tissues. Markers will be Fc and C3b receptors, NSE, and monoclonal antibodies. PROJECT E will study the biosynthesis of lipoprotein lipase, using as a model cultured differentiating pre-adipocytes, with emphasis on post-translational modification, glycosylation, regulation, adipocyte glycoprotein synthesis, enzyme purification and immunochemical localization. Core laboratories support cell culture, monocyte isolation by elutriation, macrophage culture, lipoprotein isolation purification and characterization of monocyte activation, electron microscopy, morphometry and biometry.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL026890-05
Application #
3097955
Study Section
Heart, Lung, and Blood Research Review Committee B (HLBB)
Project Start
1982-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1988-06-30
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Overall Medical
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Helmlinger, G; Berk, B C; Nerem, R M (1996) Pulsatile and steady flow-induced calcium oscillations in single cultured endothelial cells. J Vasc Res 33:360-9
Thoumine, O; Nerem, R M; Girard, P R (1995) Changes in organization and composition of the extracellular matrix underlying cultured endothelial cells exposed to laminar steady shear stress. Lab Invest 73:565-76
Marra, F; Grandaliano, G; Valente, A J et al. (1995) Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 22:780-7
Wenzel, U O; Fouqueray, B; Grandaliano, G et al. (1995) Thrombin regulates expression of monocyte chemoattractant protein-1 in vascular smooth muscle cells. Circ Res 77:503-9
Helmlinger, G; Berk, B C; Nerem, R M (1995) Calcium responses of endothelial cell monolayers subjected to pulsatile and steady laminar flow differ. Am J Physiol 269:C367-75
Thoumine, O; Nerem, R M; Girard, P R (1995) Oscillatory shear stress and hydrostatic pressure modulate cell-matrix attachment proteins in cultured endothelial cells. In Vitro Cell Dev Biol Anim 31:45-54
Schwartz, C J; Valente, A J; Hildebrandt, E F (1994) Prevention of atherosclerosis and end-organ damage: a basis for antihypertensive interventional strategies. J Hypertens Suppl 12:S3-11
Grandaliano, G; Valente, A J; Abboud, H E (1994) A novel biologic activity of thrombin: stimulation of monocyte chemotactic protein production. J Exp Med 179:1737-41
Zhu, J F; Valente, A J; Lorenzo, J A et al. (1994) Expression of monocyte chemoattractant protein 1 in human osteoblastic cells stimulated by proinflammatory mediators. J Bone Miner Res 9:1123-30
Grandaliano, G; Valente, A J; Rozek, M M et al. (1994) Gamma interferon stimulates monocyte chemotactic protein (MCP-1) in human mesangial cells. J Lab Clin Med 123:282-9

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