RTF III: Individualized Cellular Models and Epigenetic Signatures of Inflammation

Coordinators: C. Klein (UzL), F.-J. Müller (CAU), P. Rosenstiel (CAU)

RTF III develops individualized disease models in cell cultures to reproduce disease processes in the laboratory. Members are working on this with what are known as human organoids. These are cell structures that emulate organs like the intestine on an individualized basis in the petri dish. They are obtained from pluripotent stem cells or directly from the patients through biopsies. With the aid of organoids, members analyze the individual disease process and test new treatment approaches in the individualized cell culture (trial-in-a-dish). The project uses state-of-the-art functional and epigenomic analysis to characterize impaired signaling pathways and differentiation patterns in people with chronic inflammatory diseases.

What does this research area’s work build on?

RTF III is based on extensive preparatory work in the field of induced pluripotent stem cells and on work with patient material aimed at investigating the effect of genetic variation on cellular function. In particular, the focus here is on epithelial cells (surface cells that cover internal and external surfaces) and neuronal cells. Innovative methods for the manipulation of primary human and murine cells (e.g. CRISPR screens) are available for use in the Cluster.

 

What are the main research objectives?

The research area is developing scalable cellular models for important diseases of the Cluster (e.g. chronic inflammatory bowel diseases, monogenic inflammatory syndromes, neuroinflammation) and also continuing to work consistently on determining cellular differentiation patterns and activity statuses with the aid of single cell sequencing. Its main objectives are to precisely determine epigenetic changes of cell types during chronic inflammation and perform high-throughput testing of treatment-related substance libraries for the correction of complex molecular phenotypes.

 

What makes this research area special?

The combination of the members’ different areas of expertise (cell biology, neurology, internal medicine, immunology, genomics) makes the research agenda of this RTF visible at an international level. A particular focus is on epigenetic mechanisms (e.g. DNA methylation) as long-term switches controlling gene expression.

 

What does this research area contribute to precision medicine in chronic inflammation?

The research area offers an interactive process within the Cluster for the effective use of patient-specific organoids and cellular models derived from hiPSC to describe individual molecular disease phenotypes. Individual impairments in regulatory networks within the framework of inflammatory diseases (e.g. due to genetic variants) can be tested at possible intervention points. The long-term plan is to develop a systematic platform that enables users to search by individualized active principles (genotype, methylation pattern) in patient cells (“clinical trial in a dish”) or even to change these cells individually in order e.g. to transplant them back into the individual patients after reprogramming their inflammation-specific methylation patterns.

 

Cooperation with other research areas in the cluster

RTF I for genetics, RTF II for microbial analysis, RTF V for the integration of proteomics and metabolomics. RTF VI for single cell analysis.