Old friends on new paths – experimental strategies to reduce adverse effects of glucocorticoid therapy in ulcerative colitis

• Applicant: Dr. Sybille Dorothee Reichardt
• Subject Area: Gastroenterology ; Immunology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411545817

Ulcerative colitis is a disease of modern society with growing incidence that is associated with an increased risk to develop colorectal cancer. Regardless of their serious adverse effects, glucocorticoids (GC) are still widely applied to treat this disease. A targeted delivery of GC to the site of inflammation and the development of compounds with increased selectivity represent possible strategies to improve this therapy. In the preceding project we could demonstrate that GC control inflammation by acting on colonic epithelial cells, thereby indirectly influencing tumorigenesis. Due to their easy accessibility, these cells are suitable for a local application of GC. Hence, we plan to investigate the effects of rectally applied nanoparticle-encapsulated GC on DSS-induced colitis and the associated tumorigenesis, and to evaluate the potential of our approach to reduce adverse effects in comparison to budesonide. Furthermore, we will analyze GRdim mice, which are characterized by a restricted activity of GC on the molecular level. Pilot experiments revealed an earlier amelioration of disease symptoms in these mice and a reduced tumor rate. These experiments will be extended by genome-wide expression analysis by RNA-seq. Furthermore, our genetic model will be compared to the therapeutic application of two clinically relevant GC mimetics. Additional mechanistic analyses will then be conducted in a 3D in vitro model. To this end, organoids will be generated from the mucosa of the colon of GRdim mice and various cellular features will be explored in an in vitro model of inflammation. To obtain insights into the interactions between the epithelium and immune cells, organoids from the mucosa as well as tumors will be cocultured with macrophages and analyzed by using conventional and imaging flow cytometry to uncover alterations of both cell populations and the involved signaling pathways. Collectively, the envisaged experimental approaches shall pave the way to treat inflammatory bowel diseases in the future with less adverse effects also in humans.

• DFG Programme: Research Grants