The lysis of human erythrocytes by complement proteins C5b-9 is inhibited by a phosphatidylinositol-linked protein (CD59) present on the surface of these cells. We have recently detected immunologically cross-reactive and functionally-similar proteins in the plasma membranes of human platelets and endothelial cells. Our overall goal is to elucidate the structural and functional properties of these cell-surface C5b-9 inhibitors, and to determine their role in the expression and control of cell-stimulatory and procoagulant responses elicited by the C5b-9 proteins.
Our specific aims i nclude: (i) to isolate and characterize the C5b-9 inhibitor expressing CD59 antigen from human platelets, (ii) to deduce the mechanism by which CD59 (and related proteins) modulate activation of the C5b-9 complex and alter the structural and functional properties of the C5b-9 pore, (iii) to determine whether the topologic distribution of the CD59 proteins in the plasma membrane of platelets and endothelial cells is altered by cell activation, or, through their interaction with components of the C5b-9 complex, (iv) to determine whether interaction with the CD59 proteins affects the cell-stimulatory responses elicited by the bound C5b-9 proteins, and whether these cell surface components participate in vesiculation or endocytic removal of C5b-9 from the plasma membrane, (v) to determine how the cell surface expression of CD59 antigens are regulated, and whether a change in the surface concentration of these membrane proteins alters the response of platelets and endothelial cells exposed to activated complement, (vi) to determine whether exogenously added CD59 (or, functional peptide fragments derived from this protein) can inhibit the procoagulant responses of platelets and endothelial cells exposed to activated complement. It is proposed that the data derived from these studies will provide new and basic insight into the etiology of thrombotic sequelae that can accompany intravascular complement activation. Furthermore it is proposed that this research is likely to yield reagents that will prove useful for protecting platelets exposed to activated complement during storage and transfusion, and of benefit in the treatment of hypercoagulable states associated with immune and inflammatory vascular disease.
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