This is a proposal for continuation of a Program Project by a group of established investigators to study basic and clinical aspects of hemostasis and vascular biology with a focus on fibrinogen, fibrin and the vessel wall. The goal of Project 1 will be to define the structural basis of the interaction between fibrin(ogen) and FGF-2 and characterize its functional implications. Specific studies will determine associations and dissociation rate constants for the interaction, identify binding sites involved and determine if other members of the FGF family also bind fibrinogen. Other studies will determine the effect of binding of FGF-2 to fibrin(ogen) on susceptibility to proteolytic degradation and characterize the functional effects of binding including receptor interactions and angiogenesis. The next project will characterize fibrinogen as a component of the extracellular matrix. Specific studies will define the structural domains of fibrinogen and cell surface receptors required for assembly of fibrinogen into matrix, examine cell response, examine structural domains of fibrinogen and cell surface receptors required for assembly of assembly of fibrinogen into matrix, examine cell responses to matrix-associated fibrinogen and determine whether fibrinogen deposition into preformed matrix alters gene expression of matrix cells. Dr. Sporn's project is based on recent observations regarding both pro- and anti-apoptotic signaling mechanisms in endothelial cells infected with R.rickettsii. The pro-apoptotic signaling pathway directly induced by R. rickettsii infection will be characterized to determine if apoptosis involved known signaling transduction pathways involving caspase or generation of reactive oxygen species and dependency and dependency on p53. Other studies will determine if infection protects the cell from other pro-apoptotic stimuli and correlate intracellular infection, induction of apoptosis and NF-kappaB activation in cell culture and ex vivo models. Dr. Fay's project will continue detailed studies of factor VIII interactions in the intrinsic tenase complex. The functional and regulatory interactions between factor VIII and tenase will be characterized in detail. Regulation of tenase by APC will be investigated including the role of endothelial cell binding. Clinical studies will investigate diagnostic and prognostic implications of circulating fibrin(ogen) derivatives, and also evaluate new anti-thrombotic strategies in clinical trials of catheter-directed versus systemic fibrinolysis of deep vein thrombosis, lys-plasminogen as an adjunct for thrombolytic therapy of peripheral arterial occlusion and anti-coagulant strategies for prophylaxis of thrombosis with central venous catheters. The five research projects will be supported by two core facilities devoted to administration and tissue culture. The Program features a focused approach to important problems in hemostasis and vascular biology with a balance between the expertise of fundamental and clinical scientists working collaboratively.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030616-17
Application #
6183132
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
1983-07-01
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
17
Fiscal Year
2000
Total Cost
$1,554,550
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Sahni, Sanjeev K; Rydkina, Elena (2009) Host-cell interactions with pathogenic Rickettsia species. Future Microbiol 4:323-39
Sahni, Abha; Arévalo, Maria T; Sahni, Sanjeev K et al. (2009) The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells. Int J Cancer 125:577-84
Sahni, Sanjeev K; Rydkina, Elena; Sahni, Abha (2008) The proteasome inhibitor MG132 induces nuclear translocation of erythroid transcription factor Nrf2 and cyclooxygenase-2 expression in human vascular endothelial cells. Thromb Res 122:820-5
Sahni, A; Simpson-Haidaris, P J; Sahni, S K et al. (2008) Fibrinogen synthesized by cancer cells augments the proliferative effect of fibroblast growth factor-2 (FGF-2). J Thromb Haemost 6:176-83
Mosesson, M W; Hernandez, I; Raife, T J et al. (2007) Plasma fibrinogen gamma'chain content in the thrombotic microangiopathy syndrome. J Thromb Haemost 5:62-9
Rydkina, Elena; Sahni, Abha; Baggs, Raymond B et al. (2006) Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins. Infect Immun 74:5067-74
Sahni, Abha; Khorana, Alok A; Baggs, Raymond B et al. (2006) FGF-2 binding to fibrin(ogen) is required for augmented angiogenesis. Blood 107:126-31
Duan, Hai Ou; Simpson-Haidaris, Patricia J (2006) Cell type-specific differential induction of the human gamma-fibrinogen promoter by interleukin-6. J Biol Chem 281:12451-7
Clifton, Dawn R; Rydkina, Elena; Huyck, Heidie et al. (2005) Expression and secretion of chemotactic cytokines IL-8 and MCP-1 by human endothelial cells after Rickettsia rickettsii infection: regulation by nuclear transcription factor NF-kappaB. Int J Med Microbiol 295:267-78
Sahni, Abha; Sahni, Sanjeev K; Francis, Charles W (2005) Endothelial cell activation by IL-1beta in the presence of fibrinogen requires alphavbeta3. Arterioscler Thromb Vasc Biol 25:2222-7

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