TFPIalpha and TFPIbeta

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DESCRIPTION (provided by applicant): Tissue factor pathway inhibitor (TFPI) is the in vivo inhibitor of factor VIIa/tissue factor-induced coagulation and, as such, plays a critical physiologic role in regulating the coagulant and inflammatory effects of factor VIIa/tissue factor action. We have recently shown that two forms of the TFPI protein, produced by alternative mRNA splicing, are expressed in human cells. Both forms associate with the surface of cells in a glycosylphosphatidylinositol (GPI)-anchored fashion, but through different mechanisms. TFPI-alpha, a soluble protein, appears to bind to another GPI-anchored protein(s), whereas TFPI-beta contains an intrinsic GPI-anchor. The thrust of this proposal is to characterize and contrast the location, functional activity, and potential physiologic roles of TFPI-alpha and TFPI-beta. In our specific aims we propose to: 1) Compare the expression of TFP-alpha and TFPI-beta; 2) Determine the structural components of TFPR-alpha that mediate its cell surface binding; 3) Identify and characterize the TFPI-alpha surface binding protein(s); 4) Compare the activities of cell-surface TFPI-alpha and TFPI-beta, and soluble TFPI-alpha; and 5) Investigate the in vivo relevance of TFPI GPI-anchorage.