The long-term goal of this research program is to understand of the roles of coagulation and fibrinolytic factors in hemostasis, wound repair, inflammatory response, and disease pathobiology. The recent generation of viable mouse lines with selected deficits in key hemostatic factors has provided a unique opportunity to rigorously define the roles of specific factors in both physiological and disease processes. The primary objective of this research proposal is to exploit this opportunity to directly establish the importance and mechanistic role of hemostatic factors in bacterial virulence and host inflammatory response. The focus of these studies will be the bacterial pathogens, Y. pestis and S. aureus, two microorganisms that express well-described bacterial plasminogen activators, procoagulants, and fibrin(ogen) binding proteins. The project aims center on the following specific hypotheses: i) host coagulation and fibrinolytic factors are critical in bacterial virulence and pathogenesis, ii) fibrin(ogen) and plasmin(ogen) have a fundamental role in mediating host inflammatory response at sites of infection, iii) fibrin(ogen) alters inflammatory cell activity at sites of infection through the engagement of the integrin, CD11b/CD18, and iv) hemostatic factors play an important role in the inflammatory response, regardless of the challenge or tissue. These hypotheses will be tested though detailed studies of Y. pestis and S. aureus infection and host inflammatory response in mice with specific deficits in plasminogen activator, plasminogen, and fibrinogen (Specific Aims 1 and 2). The mechanistic role of fibrin(ogen)-integrin interaction in the inflammatory response will be explored by comparative studies of infection and inflammation in mice expressing mutant forms of fibrinogen lacking the motifs recognized by the platelet integrin, alphaIIbbeta3, and the leukocyte integrin, CD11b/CD18 (Specific Aims 2 and 3). Finally, the role of fibrin(ogen) in inflammatory processes unrelated to bacterial infection will be explored by studying the impact of fibrinogen deficiency on leukocyte emigration, adhesion, and function, using peritonitis and dermatitis model systems (Specific Aim 4). The proposed studies will provide a more detailed understanding of the role of coagulation/fibrinolytic factors in bacterial pathogenesis and the inflammatory response, and could ultimately lead to the development of new therapeutic strategies for the treatment of both bacterial infection and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063194-03
Application #
6390459
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$361,692
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Degen, J L; Bugge, T H; Goguen, J D (2007) Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 5 Suppl 1:24-31
Flick, Matthew J; Du, XinLi; Witte, David P et al. (2004) Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest 113:1596-606
Jirouskova, Marketa; Chereshnev, Igor; Vaananen, Heikki et al. (2004) Antibody blockade or mutation of the fibrinogen gamma-chain C-terminus is more effective in inhibiting murine arterial thrombus formation than complete absence of fibrinogen. Blood 103:1995-2002
Palumbo, J S; Zogg, M; Talmage, K E et al. (2004) Role of fibrinogen- and platelet-mediated hemostasis in mouse embryogenesis and reproduction. J Thromb Haemost 2:1368-79
Palumbo, Joseph S; Talmage, Kathryn E; Liu, Hong et al. (2003) Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency. Blood 102:2819-27
Kufrin, Dubravka; Eslin, Don E; Bdeir, Khalil et al. (2003) Antithrombotic thrombocytes: ectopic expression of urokinase-type plasminogen activator in platelets. Blood 102:926-33
Ni, Heyu; Papalia, Jessie M; Degen, Jay L et al. (2003) Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma chain. Blood 102:3609-14
Palumbo, Joseph S; Potter, Jill M; Kaplan, Lisa S et al. (2002) Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. Cancer Res 62:6966-72
Bannach, Felizabel Garcia; Gutierrez, Ana; Fowler, Bruce J et al. (2002) Localization of regulatory elements mediating constitutive and cytokine-stimulated plasminogen gene expression. J Biol Chem 277:38579-88
Drew, A F; Liu, H; Davidson, J M et al. (2001) Wound-healing defects in mice lacking fibrinogen. Blood 97:3691-8

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