Research

The Z03 project is the central part of the TRR 241, as it represents an indispensable interface between (immuno)biological and clinical information in inflammatory bowel diseases (IBD). The Z03 project developed an integrated platform that merges large scale omic-datasets from IBD patients with corresponding clinical disease status: the IBDome. The IBDome fosters translational research activities within this CRC and will allow the conceptional integration of the clinical impact on the analyzed immune-epithelial crosstalk in IBD. The database is realized on a platform. The data management hereby is done in accordance with the requirements of the EU General Data Protection Regulation and Good Scientific Practice.
The IBDome was populated in a step-wise approach: First, already existing tissue banks in Erlangen and Berlin were harmonized in their respective set-ups and recording of the clinical data was standardized. This was expanded to the structured sampling of tissues (blood, biopsie, resectates) and fecal samples. A first set of deep profiling data generated using cutting-edge technologies on a specified exemplary patient cohort including controls was analysed. This cohort consists of Crohn´s disease patients with active and inactive terminal ileitis and respective controls. The data consist of biomedical information derived from comprehensive molecular characterization of collected intestinal tissue, peripheral blood and stool using RNA sequencing, exome sequencing, 16s microbiome sequencing, mass cytometry (cytometry by time of flight; CyTOF), and histopathology. The integrated biomolecular, imaging, and clinical data (disease phenotype, disease activity, medication, complications) are available through a web-based front-end to all researchers within this CRC in order to enable further exploration of the data and generation of testable hypotheses. We envision to further develop the IBDome to a reference database for IBD during the course of the project, which will be populated with a large number of patient samples analyzed using both, deep and broad profiling. Additional cohorts are included (e.g., Crohn´s colitis, left-sided colitis, proctitis). Hence, we will provide a central resource platform not only for for the TRR 241 but also for the scientific community and thereby strengthen translational research and enable novel insights into IBD pathogenesis and ultimately the discovery of novel therapeutic strategies.

Ulcerative colitis (UC) and Crohn´s disease (CD) are the main forms of inflammatory bowel diseases. The optimal therapy depends on the diagnosis and on the follow-up. Especially in CD, magnetic resonance imaging (MRI) is the today’s technique of choice providing information about extraluminal complications and extraintestinal manifestations. Complications like fibrosis, scarring and stenosis are caused by massive remodeling of the extracellular matrix (ECM). The early prediction of deleterious ECM accumulation remains challenging in monitoring disease progress and in developing strategies for personalized treatment.
TP B06 is going to develop novel strategies addressing the ECM as integral part of the immediate surrounding for and modulated by immune cells in intestinal inflammation.
Addressing the effect of immune cells on ECM remodeling in CD, the TP B06 aims to elucidate in vivo accessible glucosaminoglycans (GAG) within the ECM that mark processes involved either in intestinal inflammation or in ECM remodeling. In-vivo imaging in mouse models combined with endoscopy and histology also in human CD will uncover distinct patterns of composition and distribution of GAG in intestinal inflammation and ECM accumulation. In the long run, GAG-related criteria will help to establish non-invasive procedures to early predict complications in CD and to suggest treatment options targeting harmful ECM to rationalize individual CD treatment. Using relevant mouse models of intestinal inflammation and comparison to human diseases, TP B06 will complete the following work program:

(1) Detection of intravenously applied VSOP in vivo, ex vivo and in situ in various tissues of mouse models of intestinal inflammation and fibrosis in correlation to the ECM, viscoelastic properties and immune cells including the crosstalk of immune cells and the ECM.

(2) Analysis of long-term effects of intravenously applied VSOP on the mucosal immune system of mice with intestinal inflammation/fibrosis.

(3) Elucidation of the diagnostic value and the sensitivity of viscoelastic properties of the inflamed gut in correlation to ECM changes and inflammation compared to ultrasound, MRI and histopathology in IBD patients.

(4) Analysis of VSOP-mediated effects on transcription and function of blood cells derived from IBD patients.

Clinician scientist program "Immune phenotyping in fistulas"
Crohn´s disease is a recurring inflammation of the whole gastrointestinal tract affecting all layers. 23-35% of the CD patients develop fistulas. A fistula is an abnormal connection of the intestine and another (hollow) organ like the bladder or the skin. Surgery is the main treatment option. So far, little is known about the development, treatment, or inflammation of fistulas. This project elucidates the immune cells infiltrating the tissue of and around a fistula. For this, imaging mass cytometry (IMC) is used as this allows the simulatenous staining and analysis of about 40 markers on tissue sections for a more comprehensive picture of the immune cells and the microenvironment. Eventually, the mechanismus of fistula development and optimal treatment options will evolve.  

On the level of experimental models, immunopathology also connects all medical subjects. This is reflected in numerous collaborations.