Protein Z (PZ) is a vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by PZ-dependent Protease Inhibitor (ZPI). ZPI is a member of the serpin superfamily of protease inhibitors and not only inhibits factor Xa in a PZ, Ca2+, and phospholipid-dependent manner, but also directly inhibits coagulation factor XIa. Evidence from mouse models demonstrates that the PZ/ZPI system plays a physiologic important role in the regulation of coagulation. The goals of this proposal are to 1) carefully characterize the role of the phospholipid surface (including that of platelets) in the anticoagulant function of PZ/ZPI, 2) determine the molecular mechanisms underlying the inhibition of factors Xa and XIa by PZ and ZPI, 3) evaluate the processes affecting the expression and plasma clearance of PZ and ZPI and, in particular, characterize their recently discovered expression in the kidney and explore its physiologic significance, and 4) further define the relationship between PZ and ZPI deficiency and thrombotic disease with an emphasis on the antiphospholipid syndrome, atherosclerosis, and potential mechanisms for the development of acquired PZ/ZPI deficiency. The work will utilize biochemical techniques, the production of recombinant, altered forms of the proteins for structure/function analysis, and mouse models to define the pathophysiologic relevance of the PZ/ZPI system. The goals of this proposal will provide important and comprehensive information, currently lacking, that will enhance our understanding of this previously unidentified pathway for the regulation of coagulation and its role in human disease.
Protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) are plasma proteins that regulate coagulation by inhibiting the action of two coagulation enzymes, factor Xa and factor XIa. The goals of this proposal are to better characterize the expression and metabolism of PZ and ZPI, determine the molecular mechanisms underlying their anticoagulant action, and further define their role in thromboembolic disease. The work will provide important information that will enhance our understanding of the regulation of coagulation by PZ and ZPI and its role in human thrombotic disease.
|Butschkau, Antje; Nagel, Philipp; Grambow, Eberhard et al. (2013) Contribution of protein Z and protein Z-dependent protease inhibitor in generalized Shwartzman reaction. Crit Care Med 41:e447-56|
|Girard, T J; Lasky, N M; Tuley, E A et al. (2013) Protein Z, protein Z-dependent protease inhibitor (serpinA10), and the acute-phase response. J Thromb Haemost 11:375-8|
|Huang, Xin; Yan, Yahui; Tu, Yizheng et al. (2012) Structural basis for catalytic activation of protein Z-dependent protease inhibitor (ZPI) by protein Z. Blood 120:1726-33|
|Sofi, Francesco; Cesari, Francesca; Abbate, Rosanna et al. (2010) A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis. Thromb Haemost 103:749-56|
|Broze Jr, G J; Tu, Y (2010) Protein Z and protein Z-dependent protease inhibitor and renal tubules. Thromb Haemost 103:473-4|
|Sofi, F; Cesari, F; Tu, Y et al. (2009) Protein Z-dependent protease inhibitor and protein Z in peripheral arterial disease patients. J Thromb Haemost 7:731-5|
|Zhang, Jing; Tu, Yizheng; Lu, Lan et al. (2008) Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency. Blood 111:4973-8|
|Piro, O; Broze Jr, G J (2005) Comparison of cell-surface TFPIalpha and beta. J Thromb Haemost 3:2677-83|
|Piro, Orlando; Broze Jr, George J (2004) Role for the Kunitz-3 domain of tissue factor pathway inhibitor-alpha in cell surface binding. Circulation 110:3567-72|
|Zhang, Jing; Piro, Orlando; Lu, Lan et al. (2003) Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 108:623-7|
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