Project Details
Projekt
(Reversible) cellular and genomic alterations induced by long-term glucocorticoid treatment
Subject Area
General Genetics and Functional Genome Biology
Cell Biology
Cell Biology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 497680553
Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR)and are widely prescribed drugs to combat inflammatory disease like rheumatoid arthritis, allergies and acute lung injury. However, their beneficial anti-inflammatory effects are accompanied by severe adverse effects (diabetes, liver steatosis, osteoporosis, muscle atrophy etc.) especially in long-term treatment schemes applied in chemotherapy, chronic inflammation or treatment of severe Coronavirus Disease 2019 (COVID-19). The project aims to understand GC-induced tissue adaptations and their reversibility in liver and lung after long-term GC treatment on a cellular and molecular level. This is relevant for patients to anticipate possible complications of GC therapy. Therefore, we will establish a cell type specific GR cistrome by the integration of whole-genome GR DNA binding data (bulk ChIP-seq) with single nuclei ATAC-seq, profiling the DNA’s accessibility, in murine liver and lung at the peak of endogenous GC concentrations and after tissue adaptation in response to long-term GC treatment. By simultaneous single nuclei RNA expression analysis (snRNA-seq) via the multiome assay (10xGenomics), we will link the cell type specific GR binding to cell type specific GC responses on the gene level. By integrating data from GR knockout mice, we will be able to describe the GR-dependent GC adverse effects at cellular resolution allowing for targeted therapy and novel insights into GC-mediated tissue alterations. Furthermore, we will elucidate if GR-induced cellular (cell type composition) and epigenetic (DNA accessibility) adaptations upon long-term GC treatment within the liver (and potentially the lung) are reversible in-vivo. We plan to investigate if persistent alterations occur which might lead to a “memory” effect with so far unknown consequences for patients undergoing GC therapy. We will establish the spatial transcriptome in murine livers upon long-term GC treatment to map cellular adaptation processes spatially in the liver and compare those to our single nuclei RNA-seq results. In the end, we plan to provide the scientific community with high quality single nuclei RNA- and ATAC-seq reference datasets for the development of tools and modeling algorithms as well as a browsable data interface.
DFG Programme
Research Grants
