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Abstract
Grant Number: 5R01HL065205-05 Project Title: ADHESION RECEPTOR POLYMORPHISMS: FUNCTIONAL STUDIES
PI Information: Name Title LOPEZ, JOSE ARON. josel@psbcresearch.org EXECUTIVE VICE-PRESIDENT OF RESEARCH Abstract: 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.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
coronary disorder, genetic polymorphism, genetic susceptibility, leukocyte adhesion molecule, platelet, selectin
atherosclerosis, disease /disorder model, disease /disorder proneness /risk, glycoprotein, ligand, neutrophil, thrombosis
cell line, clinical research, human subject, laboratory mouse
Institution: BAYLOR COLLEGE OF MEDICINE 1 BAYLOR PLAZA HOUSTON, TX 770303498 Fiscal Year: 2004 Department: MEDICINE Project Start: 30-SEP-2000 Project End: 31-JUL-2006 ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE IRG: ZHL1