Section B Project B06

Genetically-driven cell-specific activation of glucocorticoids and GR as a therapeutic tool in inflammatory arthritis

Therapeutic glucocorticoids exert potent anti-inflammatory effects and are an established therapy in many inflammatory diseases (Baschant, et al., 2011; Rauch, et al., 2010; Vettorazzi, et al., 2015). However, side effects such as osteoporosis limit their clinical use. We found that rewiring of energy metabolism by glucocorticoids is pivotal to induce resolution of inflammation (Stifel, et al., 2022) and that glucocorticoids act in the inflamed arthritic synovium via stromal cells to induce alternatively activated macrophages (Koenen, et al., 2018). This project aims to study the cell-specific responses to glucocorticoids in order to elucidate the molecular mechanism underlying glucocorticoid-induced modulation of inflammation and bone degradation. Based on preliminary data, we hypothesize that cell-specific modulation of glucocorticoid signaling in immune and stromal cells is sufficient to reduce inflammation while avoiding undesired effects. The project aims to develop a proof-of-concept for the cell-specific effects of glucocorticoids through genetic lossand gain-of function mouse models, envisioning a therapeutic cell-specific delivery of glucocorticoids or modulators of downstream signaling.