Verbatim): Plasma clotting factor VIIa (VIIa) binding to cell surface receptor tissue factor (TF) not only triggers the coagulation cascade but also induces intracellular signaling and supports cell adhesion, migration. angiogenesis and tumor metastasis. At present, it is unknown how the extracellular interactions of VIIa and TF trigger the intracellular signaling events and how these signals influence phenotype. One possible mechanism is that VIIa/TF, through proteolytic activation of a cell surface receptor, akin to a protease activated receptor, induces expression of growth regulators that act as downstream mediators of VIIa-induced cellular responses. Our preliminary studies (J Biol. Chem. 275: 14632-14641, 2000) that employ cDNA microarray technology show that exposure of fibroblasts to VIIa induces the expression of Cyr6l and connective tissue growth factor (CTGF,) Cyr6I and CTGF comprise prototypes of a highly conserved new family of extracellular matrix signaling proteins that regulate various biological processes, such as cell adhesion, proliferation, migration, angiogenesis and tumor growth. In this application, we propose to analyze the details of the VIIa-induced expression of Cyr6l and CTGF and determine the role of these proteins in mediating VIIa-induced biological processes.
Specific Aim 1 test whether the VIIa-induced expression of Cyr6l and CTGF involves the activation of PAR2 and define the pathways involved in the protease-induced expression of Cyr6l and CTGF.
Specific Aim 2 identifies and characterizes VIIa-responsive element(s) in Cyr6l and CTGF genes.
Specific Aim 3 tests the hypothesis that the VIIa-induced expression of Cyr6l and CTGF are responsible for the VIIa-induced cell adhesion, proliferation and migration of fibroblasts.
Specific Aim 4 tests a hypothesis that Cyr6 1 and/or CTGF act as downstream mediators in the VIIa/TF-induced tumor metastasis. The fundamental knowledge derived by these studies will aid in understanding how VIIa/TF participates in a number of pathophysiological processes. In long term, understanding the molecular details of the VIIa/TF-induced signaling pathways could lead to the development of new therapeutic approaches that intervene with deleterious actions of VIIa/TF that contribute to pathogenesis of various diseases, such as atherosclerosis, metastasis and angiogenesis, without compromising the integrity of hemostatic system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065500-01A1
Application #
6327228
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
2001-09-01
Project End
2005-07-31
Budget Start
2001-09-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$195,179
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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Rao, L Vijaya Mohan; Kothari, Hema; Pendurthi, Usha R (2012) Tissue factor encryption and decryption: facts and controversies. Thromb Res 129 Suppl 2:S13-7
Rao, L V M; Pendurthi, U R (2012) Regulation of tissue factor coagulant activity on cell surfaces. J Thromb Haemost 10:2242-53
Rao, L Vijaya Mohan; Kothari, Hema; Pendurthi, Usha R (2012) Tissue factor: mechanisms of decryption. Front Biosci (Elite Ed) 4:1513-27
Kothari, Hema; Rao, L Vijaya Mohan; Vankayalapati, Ramakrishna et al. (2012) Mycobacterium tuberculosis infection and tissue factor expression in macrophages. PLoS One 7:e45700
Sen, Prosenjit; Gopalakrishnan, Ramakrishnan; Kothari, Hema et al. (2011) Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 117:3199-208
Sen, P; Komissarov, A A; Florova, G et al. (2011) Plasminogen activator inhibitor-1 inhibits factor VIIa bound to tissue factor. J Thromb Haemost 9:531-9
Kothari, H; Rao, L V M; Pendurthi, U R (2011) Glycosylation of tissue factor is not essential for its transport or functions. J Thromb Haemost 9:1511-20
Tucker, Torry A; Dean, Candice; Komissarov, Andrey A et al. (2010) The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells. Am J Respir Cell Mol Biol 42:685-96

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