Platelet and Ieukocyte adhesion are involved in every phase of arterial thrombosis, from the formation of the atherosclerotic lesion that initiates the process, to the development of the thrombus that occludes a vital blood vessel and causes tissue infarction. These cells can adhere to cells of the same type, to each other, and to the vessel wall. We have discovered that the platelet receptor that mediates the initial adhesion of platelets to the injured blood vessel wall, the GP Ib-IX-V complex, also binds key counter receptors on endothelium (P-selectin) and on leukocytes (L-selectin and the leukocyte integrin Mac-I). The ligand-binding subunit of this complex, GP Ibalpha, has three polymorphic sites, each of which affect either the structure of the polypeptide (the VNTR length polymorphism and the Ko alloantigen polymorphism) or the expression of the receptor on the platelet surface (the Kazak polymorphism, which influences the translational efficiency of the GP Ibalpha mRNA). We have also found that a related leukocyte adhesion molecule Pselectin glycoprotein ligand-1 (PSGL-1), which mediates the initial adhesion of neutrophils and monocytes to inflamed endothelium, has a polymorphism very similar to the VNTR polymorphism of OP The. Both of these membrane sialomucins play extremely important roles in blood cell interaction with the vessel wall, and we expect that the polymorphisms will influence their functions and thus also the likelihood of developing atherosclerosis and arterial thrombosis. We therefore propose to define the functional consequences by studies in both cell lines, platelets and neutrophils and to determine whether the polymorphisms are associated with risk for developing coronary heart disease in a large community based study. Finally, we will attempt to develop mouse models of arterial thrombotic disease and study the role of the GP Ibalpha VNTR polymorphism is modulating the propensity for atherosclerosis and thrombosis in this model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065205-01
Application #
6152982
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Jacobs, Tom P
Project Start
2000-09-30
Project End
2005-07-31
Budget Start
2000-09-30
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$336,375
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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