The application proposes to elucidate the molecular mechanisms which cause sickle red blood cells to adhere to vascular endothelium. It is clear that this phenomenon may contribute to the clinical problems of sickle vascular crises, and improved understanding of the molecules involved in this process may lead to new therapeutic approaches. The investigators will focus their efforts on the probable role of basal cell adhesion molecule which is also the molecular site of the Lutheran antigens (B-CAM/LU) and the extracellular protein laminin. They will seek to define the molecular epitopes responsible for this association and to establish whether there is ancillary involvement of protein CD44. Similarly, they will seek to define the molecular interactions of integrin associated protein (IAP) with thrombospondin. Finally, they will evaluate the associations of these and other membrane proteins under simulated physiological conditions by measuring the associations of these molecules with extracellular matrix and with disrupted vascular endothelium using a flow chamber model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058939-04
Application #
6183349
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1997-08-13
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$337,999
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Zennadi, Rahima; Moeller, Benjamin J; Whalen, Erin J et al. (2007) Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo. Blood 110:2708-17
Murphy, Meghan M; Zayed, Mohamed A; Evans, Allyson et al. (2005) Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood 105:3322-9
Zen, Qin; Batchvarova, Milena; Twyman, Christina A et al. (2004) B-CAM/LU expression and the role of B-CAM/LU activation in binding of low- and high-density red cells to laminin in sickle cell disease. Am J Hematol 75:63-72
Zennadi, Rahima; Hines, Patrick C; De Castro, Laura M et al. (2004) Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood 104:3774-81
Hines, Patrick C; Zen, Qin; Burney, Sharran N et al. (2003) Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion. Blood 101:3281-7
Garratty, George; Telen, Marilyn J; Petz, Lawrence D (2002) Red cell antigens as functional molecules and obstacles to transfusion. Hematology Am Soc Hematol Educ Program :445-62
Brittain, J E; Mlinar, K J; Anderson, C S et al. (2001) Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin. Blood 97:2159-64
Brittain, J E; Mlinar, K J; Anderson, C S et al. (2001) Activation of sickle red blood cell adhesion via integrin-associated protein/CD47-induced signal transduction. J Clin Invest 107:1555-62
Telen, M J (2000) Red blood cell surface adhesion molecules: their possible roles in normal human physiology and disease. Semin Hematol 37:130-42
Zen, Q; Cottman, M; Truskey, G et al. (1999) Critical factors in basal cell adhesion molecule/lutheran-mediated adhesion to laminin. J Biol Chem 274:728-34

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