This proposal is for a Program Project to study basic aspects and interrelations of coagulation proteins, especially fibrinogen, thrombin, von Willebrand protein and Factor VIII, and to apply new findings and insights to clinical investigations, principally relating to the hemophilias and to fibrinogen as it is involved in thrombohemorrhagic disorders. The proposal has evolved from interactions between scientists working in proximity toward similar goals as part of three existing independent NHLBI grants. These effforts have been reorganized and expanded in order to facilitate and encourage further progress in these studies. In addition to the four basic research projects, there are four applied clinical projects (combined into Project 5), dealing with new fibrinolytic agents or modes of therapy of coronary artery thrombi, the structure of fibrin thrombi and circulating crosslinked fibrin derivatives, a search for pathogenetic mechanisms in skin capillary endothelial cells of patients with von Willebrand's disease, and infusion and biologic turnover studies of human Factor VIII in animals with hemophilia or von Willebrand's disease. There are four Core facilities for administration, cell culture, hybridoma/monoclonal antibody production and physical chemical characterization. The facilities are primarily located in the Hematology Unit of the University of Rochester, with a close affiliation with the Chemistry Department at Cornell University (Ithaca, New York). The key investigaors provide scientific direction for the program and are comprised of four M.D.'s and four Ph.D.'s primarily biochemists and cell biologists, in the common goal of a better understanding of molecular structure and function relationships of the coagulation proteins, both individually and as interacting moities with each other or with other proteins such as fibronectin. The proposed clinical studies will address the important conditions of Factor VIII-related hemorrahagic states and the formation and treatment of thrombotic vascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of Rochester
School of Medicine & Dentistry
United States
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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
Fay, Philip J; Jenkins, P Vincent (2005) Mutating factor VIII: lessons from structure to function. Blood Rev 19:15-27
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

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