Fibrinogen is a multifunctional protein involved in a number of important physiological and pathological processes. The formation of a fabrin matrix at sites of tissue injury (or other places) prevents blood loss and provides a provisional stroma that interacts with different cell types to promote their deposition, migration and proliferation. Thus, besides its prominent function in hemostasis, fibrinogen is recognized as a cell adhesion molecule that plays an important role in inflammation, angiogenesis, wound healing, atherogenesis and tumorigenesis. Despite numerous studies, several basic problems important for a comprehensive understanding of its biological functions are still unresolved. This application deals with three such problems: (1) a high resolution structure, (2) the molecular mechanisms of conversions of fibrinogen to fibrin, and (3) the mechanisms of interactions of fabrin(ogen) with different cell types.
The first aim i s to establish the high resolution structure of the central E regions of fibrinogen and its alpha-C domains.
The second aim i s to elucidate the mechanisms of fibrinogen to fabrin conversions which is hypothesized to involve a switch from intra- to intermolecular binding between alpha-C domains as well as conformation changes in the D region that modulate activity of the secondary polymerization sites and expression of new interaction sites.
The third aim focuses on establishing the mechanisms of interaction of endothelial cells and leukocytes with fibrinogen and fibrin and identification of critical amino acid residues involved.
These aims will be accomplished by preparation of various fibrinogen domains and combinations there of by limited proteolysis and recombinant techniques, and studying their structures and interactions by biochemical and biophysical methods. These studies will generate basic knowledge that will have an impact on the understanding of and ability to control different fibrinogen-dependent processes. They will also have an important practical health-related application to the development of improved bioadhesives (fibrin glue) by the de novo design of fibrinogen with selected functions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056051-05
Application #
6490565
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
1998-01-01
Project End
2003-08-03
Budget Start
2002-01-01
Budget End
2003-08-03
Support Year
5
Fiscal Year
2002
Total Cost
$326,692
Indirect Cost
Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20006
Yakovlev, Sergiy; Medved, Leonid (2018) Effect of fibrinogen, fibrin, and fibrin degradation products on transendothelial migration of leukocytes. Thromb Res 162:93-100
Yakovlev, Sergiy; Medved, Leonid (2017) Interaction of Fibrin with the Very Low-Density Lipoprotein (VLDL) Receptor: Further Characterization and Localization of the VLDL Receptor-Binding Site in Fibrin ?N-Domains. Biochemistry 56:2518-2528
Yakovlev, Sergiy; Belkin, Alexey M; Chen, Ling et al. (2016) Anti-VLDL receptor monoclonal antibodies inhibit fibrin-VLDL receptor interaction and reduce fibrin-dependent leukocyte transmigration. Thromb Haemost 116:1122-1130
Yakovlev, Sergiy; Medved, Leonid (2015) Interaction of Fibrin with the Very Low Density Lipoprotein Receptor: Further Characterization and Localization of the Fibrin-Binding Site. Biochemistry 54:4751-61
Yakovlev, S; Mikhailenko, I; Tsurupa, G et al. (2014) Polymerisation of fibrin ?C-domains promotes endothelial cell migration and proliferation. Thromb Haemost 112:1244-51
Yakovlev, Sergiy; Mikhailenko, Irina; Cao, Chunzhang et al. (2012) Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes. Blood 119:637-44
Tsurupa, Galina; Pechik, Igor; Litvinov, Rustem I et al. (2012) On the mechanism of ?C polymer formation in fibrin. Biochemistry 51:2526-38
Tsurupa, Galina; Mahid, Ariza; Veklich, Yuri et al. (2011) Structure, stability, and interaction of fibrin ?C-domain polymers. Biochemistry 50:8028-37
Riedel, Tomas; Suttnar, Jiri; Brynda, Eduard et al. (2011) Fibrinopeptides A and B release in the process of surface fibrin formation. Blood 117:1700-6
Yakovlev, S; Gao, Y; Cao, C et al. (2011) Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments. J Thromb Haemost 9:1847-55

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