Abstract

Tissue factor pathway inhibitor (TFPI) is a critical regulator of tissue factor induced coagulation. The overall goals of this proposal are to further delineate the structures within the TFPI molecule that mediate its specific functional properties and to better define the physiologic role of TFPI through the use of mouse models.
The specific aims are: 1) determine the structure of 34 kDa TFPI bound in plasma by low density lipoproteins (LDL) and determine the mechanisms underlying this association; 2) investigate the mechanisms of TFPI association with cell surfaces by examining the structure and properties of a mammalian expressed rTFPI which lacks this attribute; 3) further characterize TFPIK1 gene-disrupted mice which have an isolated deficiency in TFPI-mediated factor VIIa/TF inhibition; 4) produce TFPI null mice and compare their phenotype with that of TFPIK1 mice; and 5) attempt to rescue TFPIK1 (-/-) mice from intrauterine mortality with doxycycline-regulated transgene expression of TFPI to permit the evaluation of the physiologic role of TFPI in adult animals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034462-16
Application #
6183669
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
16
Fiscal Year
2000
Total Cost
$358,557
Indirect Cost

  Institution

Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110

  Publications

Ndonwi, M; Broze Jr, G (2008) Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor. J Thromb Haemost 6:1044-6
Ndonwi, Matthew; Broze Jr, George J; Agah, Sayeh et al. (2007) Substitution of the Gla domain in factor X with that of protein C impairs its interaction with factor VIIa/tissue factor: lack of comparable effect by similar substitution in factor IX. J Biol Chem 282:15632-44
Ndonwi, M; Broze Jr, G; Bajaj, S P (2005) The first epidermal growth factor-like domains of factor Xa and factor IXa are important for the activation of the factor VII--tissue factor complex. J Thromb Haemost 3:112-8
Lu, Genmin; Broze Jr, George J; Krishnaswamy, Sriram (2004) Formation of factors IXa and Xa by the extrinsic pathway: differential regulation by tissue factor pathway inhibitor and antithrombin III. J Biol Chem 279:17241-9
Forastiero, R R; Martinuzzo, M E; De Larranaga, G et al. (2003) Antibodies to tissue factor pathway inhibitor are uncommonly detected in patients with infection-related antiphospholipid antibodies. J Thromb Haemost 1:2250-1
Forastiero, R R; Martinuzzo, M E; Broze, G J (2003) High titers of autoantibodies to tissue factor pathway inhibitor are associated with the antiphospholipid syndrome. J Thromb Haemost 1:718-24
Forastiero, R R; Martinuzzo, M E; Lu, L et al. (2003) Autoimmune antiphospholipid antibodies impair the inhibition of activated factor X by protein Z/protein Z-dependent protease inhibitor. J Thromb Haemost 1:1764-70
Eitzman, Daniel T; Westrick, Randal J; Bi, Xiaoming et al. (2002) Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden. Circulation 105:2139-42
Westrick, R J; Bodary, P F; Xu, Z et al. (2001) Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation 103:3044-6
Chan, J C; Carmeliet, P; Moons, L et al. (1999) Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit. J Clin Invest 103:475-82

Showing the most recent 10 out of 47 publications