Genomes and Genes
PATHOLOGICAL CONSEQUENCES OF THE PLASMINOGEN SYSTEM
Principal Investigator: Victoria Ploplis
Abstract: The long-term goal of this proposal is to identify functions and determine mechanisms of the fibrinolytic system, and its inhibitors, in physiological and pathological processes utilizing cell-based and in vivo models. The availability of mice with deficiencies of genes of the fibrinolytic system has resulted in direct analyses of the role of these proteins in a number of biological events. Studies have indicated that a PAI-1 deficiency diminishes angiogenesis in tumor models. Further, our laboratory has shown that endothelial cell (EC) signaling and function are regulated by PAI-1/LRP interactions. The current application will further elucidate effects of PAI-1 on cell signaling pathways and determine the importance of PAI-1/LRP interactions in both cellular and physiological events. As a result of these observations, the following studies are proposed: (1.) Determine the effects of a PAI-1 deficiency on murine EC JAK/STAT signaling and cell cycle progression. These studies will assess STAT and JAK expression profiles and activation status in proliferating wild-type (WT) and PAI-1-/- EC as well as the extent of nuclear translocation of STAT. The addition of rPAI-1 and mutants will determine which functional domains of PAI-1 regulate the activation status of this pathway. Additional studies will determine effects on cell migration. Downstream effects on cell cycle progression will also be investigated. The hypothesis is that a PAI-1 deficiency will affect JAK/STAT signaling and downstream cell cycle progression, and that these effects are mediated by PAI-1/LRP interactions. (2.) Characterize early and late stage events of cardiac fibrosis in PAI-1-/- and uPA-/-/PAI-1-/- mice. Recent studies have shown that PAI-1-/- mice develop cardiac fibrosis, which may be mediated by dysregulated uPA or chronic activation of the Akt pathway, the result of altered PAI-1/LRP interactions. The studies proposed will initially characterize cardiac fibrosis in PAI-1-/- and uPA-/-/PAI-1-/- mice in order to differentiate effects from uPA activity and PAI-1 functions independent of uPA inhibition in cardiac fibrosis phenotypes. The hypothesis is that cardiac fibrosis will be regulated by urokinase activity and other functions of PAI-I which will be further pursued in future studies of mice expressing functional mutations of PAI-1.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
- Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in miceR D Balsara
W M Keck Center for Transgene Research, University of Notre Dame, Indiana 46556, USA
Curr Drug Targets 8:982-95. 2007....
- Plasminogen activator inhibitor-1: the double-edged sword in apoptosisRashna D Balsara
W M Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
Thromb Haemost 100:1029-36. 2008..Moreover, results from studies assessing the role of PAI-1 in apoptosis have suggested that PAI-1 can exert pathogenic or protective effects, which may be related to the disease model or type of injury employed...
- The vitronectin-binding domain of plasminogen activator inhibitor-1 plays an important functional role in lipopolysaccharide-induced lethality in miceR Narasaki
W M Keck Center for Transgene Research Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
J Thromb Haemost 10:2618-21. 2012..The vitronectin-binding domain of plasminogen activator inhibitor-1 plays an important functional role in lipopolysaccharide-induced lethality in mice. J Thromb Haemost 2012; 10: 2678-21...
- Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architectureZhi Xu
The W M Keck Center for Transgene Research, 230 Raclin Carmichael Hall, University of Notre Dame, Notre Dame, IN 46556, USA
Blood 115:2038-47. 2010....
- Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular diseaseVictoria A Ploplis
W M Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
Curr Drug Targets 12:1782-9. 2011..Further investigations involving regulation of cell function could potentially resolve paradoxical issues associated with the function of this protein in regulating cardiovascular disease...