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.
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| Gopalakrishnan, R; Hedner, U; Clark, C et al. (2010) rFVIIa transported from the blood stream into tissues is functionally active. J Thromb Haemost 8:2318-21 |
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