Generation and detailed analysis of novel tools to study the importance of dimerization of the Glucocorticoid Receptor in inflammation. 

Since Systemic Inflammatory Response Syndrome (SIRS), such as sepsis, is by definition an inflammatory disease, it is bizarre that Glucocorticoids (GCs) are ineffective in this context. To generate more effective GCs, over the past 25 years, the emphasis has been on the generation of GR ligands that favor GR monomer formation (referred to as SElective GR Agonists, SEGRAs). This has not resulted in a successful therapy. Our observations indicate that, at least for the treatment of SIRS, we should go in the opposite direction by generating SElective DImerizing GR Agonists (= SEDIGRAs). To be able to do this, it is also necessary to understand the process of GR dimerization and to study what will be the impact of increasing the ratio of GR dimers/GR monomers in cells and in animals. In this project, we will generate and analyze novel tools to study the importance of dimerization of the GR in inflammation. A system by which we can control the ratio of GR dimers/GR monomers will be created based on the iDIMERIZE system. The effect of different degrees of GR dimerization will be tested in vitro. Based on the same system, we will generate mice with chemically inducible GR dimerization (GRcid) by the use of the CRISPR/Cas9 technology. Because we are interested in acute inflammation, we will study these mice in SIRS models. These mice will be phenotyped and the hope is that the chemically induced GR dimerization in combination with GCs will lead to a complete control of SIRS.