The long-term goal of this research program is to use gene-targeting and gene-transfer technologies in mice to directly test the following general hypothesis: hemostatic factors are critical in the progression and pathobiology a wide spectrum of diseases, including atherosclerosis, cancer, fibrotic lung disease, sickle cell disease, and other diseases associated with acute or chronic tissue injury. The specific objective of this research plan is to directly test the hypothesis that two key hemostatic factors, fibrinogen (Fib) and plasminogen (Plg), are important in the progression of vessel wall disease. A substantial amount of indirect evidence has pointed to a critical role of hemostatic factors in the early progression of atherosclerotic disease that generally precedes and predisposes to myocardial infarction and stroke, including the presence of copious amounts of fibrin(ogen) and fibrin degradation products within early lesions, high local expression of procoagulants and fibrinolytic system components, epidemiological identification of specific hemostatic factors as risk factors for coronary artery disease, and the incorporation of mural thrombi into advanced plaques. The recent generation of gene-targeted mouse lines predisposed to atherosclerosis as a consequence of selected deficiencies in apolipoproteins or their receptors, coupled with the availability of mice with selected deficits in key hemostatic factors, has provided an opportunity to directly test the importance of specific coagulation and fibrinolytic factors in atherosclerosis in vivo.
In Specific Aim 1 of this proposal, the progression of atherosclerotic disease will be quantitatively and qualitatively compared in LDLR-deficient and control C57B1/6 mice that either retain or lack Fib and Plg. Age, diet, and gender will be examined as independent variables in these studies. The mechanistic role of fibrin(ogen) in the acceleration of atherosclerosis observed in Plg-deficient mice will be determined in Specific Aim 2 by detailed analysis of atherosclerotic disease in mice with single and combined deficiencies in those hemostatic factors.
In Specific Aim 3, the impact of Fib and Plg deficiencies on neointima formation following chronic inflammatory challenge will be evaluated. The proposed studies will provide a more detailed understanding of the role of specific coagulation/fibrinolytic factors in vascular disease and could ultimately lead to new and valuable therapeutic strategies for the prevention and treatment of vascular disorders causing life-threatening arterial occlusion.
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