This application proposes to study the regulation of plasminogen expression at the protein, MRNA and transcriptional level in both in vitro and in vivo systems. This protein is a key player in the fibrinolytic system which mediates intravascular fibrin degradation as well as degradation of extracellular matrix, essential components of wound healing, tissue remodeling and inflammatory processes. Preliminary data demonstrate for the first time that plasminogen gene expression is regulated by mediators induced during the inflammatory response, indicating that fibrinolytic activity may be regulated by changes in the expression of plasminogen. This is supported by the observations that plasminogen deficiency is correlated with an increased risk of thrombosis and that populations showing a decreased incidence of coronary heart disease are associated with higher plasminogen levels. The proposal will test the hypothesis that expression of the plasminogen gene is regulated by inflammatory mediators both in the liver and extrahepatic tissues.
The specific aims are 1) to test the hypothesis that plasminogen expression is regulated in response to inflammatory mediators by characterizing plasminogen expression in hepatocytes and monocytes and correlating this expression with functional activities; 2) to test the hypothesis that one or more cis-acting elements are responsible for the response of the plasminogen gene to specific inflammatory mediators and to identify transcription factors which mediate the response; 3) to test the hypotheses, i) that the plasminogen gene is regulated in vivo in the mouse in response to inflammatory mediators, ii) that endogenous cytokine production in the CNS stimulates plasminogen gene expression using transgenic mice overexpressing IL-6 in the brain and iii) that plasminogen is required for the neuropathology observed in mice overexpressing IL-6 by crossing IL-6 overproducing mice with plasminogen-deficient mice.
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