This application addresses broad Challenge Area 06: Enabling Technologies and the specific Challenge Topic 06-HL-105: Develop transgenic animal models that are informative for understanding chronic inflammation in humans. A new generation of highly selective, protease-specific anticoagulant drugs is entering clinical applications, but we have an incomplete understanding of how these drugs attenuate inflammatory processes in cardiovascular diseases, obesity, autoimmune disorders and cancer. There has been recent progress in understanding the role of coagulation protease signaling in acute inflammation. However, the evaluation of these pathways in chronic inflammation has been hampered by the lack of a comprehensive repertoire of knock-in mouse models that specifically probe coagulation signaling. Based on our recent success to selectively ablate limbs within the network of coagulation signaling responses mediated by the thrombin receptor, we here propose a new strategy that will generate an expanded set of mouse strains to evaluate the signaling specificity of other coagulation proteases. This targeted short term research provides an opportunity to generate tools that will enable a new level of understanding of the role of coagulation proteases in chronic inflammation and advance innovative research on how protease-selective therapeutics interfere with these signaling networks in disease. Chronic inflammation is contributing to the development of highly prevalent cardiovascular and other diseases. The hemostatic system is fine tuning inflammatory reactions by cell signaling events that change the function of the vascular endothelium as well as immune cells. A comprehensive repertoire of genetic models for coagulation protease signaling will enable testing of innovative therapeutic strategies to interrupt diverse disease processes that are fueled by chronic inflammation.
Chronic inflammation is contributing to the development of highly prevalent cardiovascular and other diseases. The hemostatic system is fine tuning inflammatory reactions by cell signaling events that change the function of the vascular endothelium as well as immune cells. A comprehensive repertoire of genetic models for coagulation protease signaling will enable testing of innovative therapeutic strategies to interrupt diverse disease processes that are fueled by chronic inflammation.
| Disse, Jennifer; Petersen, Helle Heibroch; Larsen, Katrine S et al. (2011) The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 286:5756-67 |
| Disse, J; Ruf, W (2011) Endothelial protein C receptor is required for tissue factor ternary complex signaling in the mouse. J Thromb Haemost 9:2516-8 |
