Abstract

The goal of this proposal is to test the hypothesis that elevated fibrinogen, either alone or with a predisposition to atherosclerosis, causes or contributes to cardiovascular diseases. To do this, three mouse models with elevated fibrinogen levels will be developed and examined. The first model, a transgenic model that contains randomly inserted copies of the murine fibrinogen genes, will be created by pronuclear injection of fertilized mouse embryos. A second model with a specific targeted duplication of the murine fibrinogen gene locus in embryonic stem cells and resultant altered animals will be generated according to a recently developed targeted duplication procedure. A third model of hyperfibrinogenemia with a combined deficiency in apolipoprotein E will be constructed by cross breeding hyperfibrinogenemic mice with apolipoprotein E null mice. The incidence of atherosclerosis and progression of the disease will be assessed morphometrically in these genetically altered mice by measurements of atherosclerotic lesion size and percent surface area of the aorta affected.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052706-02
Application #
2857837
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
1999-01-15
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Gulledge, Alyssa A; McShea, Cynthia; Schwartz, Todd et al. (2003) Effects of hyperfibrinogenemia on vasculature of C57BL/6 mice with and without atherogenic diet. Arterioscler Thromb Vasc Biol 23:130-5
Hogan, Kelly A; Weiler, Harmut; Lord, Susan T (2002) Mouse models in coagulation. Thromb Haemost 87:563-74
Gulledge, A A; Rezaee, F; Verheijen, J H et al. (2001) A novel transgenic mouse model of hyperfibrinogenemia. Thromb Haemost 86:511-6
Lord, S T; Gorkun, O V (2001) Insight from studies with recombinant fibrinogens. Ann N Y Acad Sci 936:101-16
Hogan, K A; Maeda, N; Kluckman, K D et al. (2001) Synthesis of a mouse model of the dysfibrinogen Vlissingen/Frankfurt IV. Ann N Y Acad Sci 936:117-21
Hogan, K A; Gorkun, O V; Lounes, K C et al. (2000) Recombinant fibrinogen Vlissingen/Frankfurt IV. The deletion of residues 319 and 320 from the gamma chain of firbinogen alters calcium binding, fibrin polymerization, cross-linking, and platelet aggregation. J Biol Chem 275:17778-85