Tissue Factor Pathway Inhibitor (TFPI) is an endothelial associated anticoagulant protein that directly inhibits the Tissue Factor-factor VIIa (TF-fVIIa) catalytic complex preventing intravascular thrombosis, disseminated intravascular coagulation, tumor metastasis and other pathologies associated with production of TF within the vasculature. TF-fVIIa activates blood clotting via cleavage of factors IX and X and initiates inflammation via activation of Protease Activated Receptors (PARs). Our long-term goal is to develop methods for prevention and treatment of the adverse effects of intravascular TF activity based upon understanding its pathobiology through studies of its inhibition by TFPI. TFPI is made in three alternatively spliced isoforms that differ in their tissue distribution, domain structure, and mechanism for cell surface association. We hypothesize that examination of structurally diverse forms of TFPI with distinct mechanisms for cell surface association will reveal variable efficacies in their ability to inhibit TF-mediated pro-coagulant and/or pro-inflammatory activity. By characterizing the unique features of how TFPI down-regulates TF activity we will better understand the pathogenesis of diseases mediated by intravascular expression of TF.
Three Specific Aims are designed to define the functions of different forms of TFPI using both in vitro and in vivo model systems. SA1 will compare the anti-TF activity of different forms of GPI-anchored TFPI on the surface of CHO cells and primary mouse endothelial cells. SA2 will examine how the mode of membrane association (GPI-anchored vs. transmembrane) TFPI activity on CHO cells, aerolysin resistant EA.hy926 cells and primary mouse endothelial cells. Studies will also be performed to examine how caveolin-1 and the GPI-anchored co- receptor for TFPI-alpha impact TFPI inhibitory activity. In SA3 we will produce transgenic mice specifically expressing TFPI-alpha or TFPI-beta using an inducible and reversible tetracycline controlled transactivator system. The transgenic mice will be bred with TFPI(+/-) mice to determine if there is isoform specific rescue of embryonic lethality.
This proposal is relevant to public health as it investigates cellular responses to injury and inflammation, balancing the development of blood clots necessary to prevent severe bleeding while at the same time avoiding the development of intravascular blood clots that can result in heart attack or stroke and enhance tumor metastasis.
|Wood, Jeremy P; Ellery, Paul E R; Maroney, Susan A et al. (2014) Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-* but not for cell surface-associated tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 34:169-76|
|Wood, Jeremy P; Ellery, Paul E R; Maroney, Susan A et al. (2014) Biology of tissue factor pathway inhibitor. Blood 123:2934-43|
|Ellery, Paul E R; Maroney, Susan A; Martinez, Nicholas D et al. (2014) Translation of human tissue factor pathway inhibitor-* mRNA is controlled by alternative splicing within the 5' untranslated region. Arterioscler Thromb Vasc Biol 34:187-95|
|Wood, Jeremy P; Bunce, Matthew W; Maroney, Susan A et al. (2013) Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci U S A 110:17838-43|
|Maroney, S A; Ellery, P E; Wood, J P et al. (2013) Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI)* and TFPI*. J Thromb Haemost 11:911-8|
|Reshetnyak, Andrey V; Nelson, Bryce; Shi, Xiarong et al. (2013) Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region. Proc Natl Acad Sci U S A 110:17832-7|
|Maroney, Susan A; Hansen, Karen G; Mast, Alan E (2013) Cellular expression and biological activities of alternatively spliced forms of tissue factor pathway inhibitor. Curr Opin Hematol 20:403-9|
|Maroney, Susan A; Ellery, Paul E; Wood, Jeremy P et al. (2012) Caveolae optimize tissue factor-Factor VIIa inhibitory activity of cell-surface-associated tissue factor pathway inhibitor. Biochem J 443:259-66|
|Maroney, Susan A; Cooley, Brian C; Ferrel, Josephine P et al. (2012) Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia. Proc Natl Acad Sci U S A 109:3927-31|
|Maroney, Susan A; Cooley, Brian C; Ferrel, Josephine P et al. (2011) Murine hematopoietic cell tissue factor pathway inhibitor limits thrombus growth. Arterioscler Thromb Vasc Biol 31:821-6|
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