The long-term objective of this research is to determine the in vivo role of coagulation factors, specifically that of Factor VII (FVII). FVII is generally accepted to play a key role in the initiation of coagulation following vascular injury. The overall goal of the proposed research is examine in detail the initiation of coagulation and hemostatic response after vascular injury and inflammatory challenge in the presence or absence of FVII. The approach to the problem is to utilize recently generated FVII- and FIX-deficient mice. FVII(-/-), FXI(-/-), FVII(-/-)/FXI(-/-) and wild-type mice will be examined after vascular injury. Thrombus formation and fibrin deposition will be monitored. This strategy will reveal the critical roles of FVII by identifying which processes are impaired in the absence of FVII. Furthermore, by genetically blocking FVII-initiated coagulation, it will be possible to identify whether and to what extent FXI contributes to the initiation of coagulation and thrombus formation. In addition, several elements in the coagulation pathway have been shown to affect embryogenesis. While FVII-deficient and FXI-deficient mice develop normally, it is proposed to determine if simultaneous knockout of both known coagulation initiating pathways result in embryonic lethality. Normal development of FVII/FXI-deficient double gene deletions might suggest alternative mechanisms to initiate the coagulation cascade during embryogenesis. Coagulation is involved in many normal and pathophysiological conditions including hemostasis, thrombosis, inflammation, atherosclerosis, and cancer. The proposed research will contribute to our understanding of elements contributing to coagulation initiation in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL060081-04
Application #
6845229
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2004-01-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$163,806
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Rosen, Elliot D; Xu, Haifeng; Liang, Zhong et al. (2005) Generation of genetically-altered mice producing very low levels of coagulation factorVII. Thromb Haemost 94:493-7
Rosen, E D; Cornelissen, I; Liang, Z et al. (2003) In utero transplantation of wild-type fetal liver cells rescues factor X-deficient mice from fatal neonatal bleeding diatheses. J Thromb Haemost 1:19-27
Castellino, Francis J; Liang, Zhong; Volkir, S Patrick et al. (2002) Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost 88:462-72
Rosen, Elliot D; Gailani, Dave; Castellino, Francis J (2002) FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost 87:774-6