Inflammatory activity and targeting of the extracellular matrix in chronic inflammatory bowel diseases
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Project content
Ulcerative colitis and Crohn's disease are the main forms of chronic inflammatory bowel disease. Optimal treatment of these diseases requires reliable diagnosis and monitoring. Especially in Crohn's disease, magnetic resonance imaging (MRI) is today's tool of choice, as it provides information on extraluminal complications and extraintestinal manifestations. Complications such as fibrosis, scarring and stenosis are caused by massive remodelling of the extracellular matrix. Detecting these changes in time remains challenging. Early prediction of this deleterious accumulation of the extracellular matrix would not only allow improved monitoring of disease progression, but also the development of strategies for personalised treatment.
Therefore, SP B06 will develop novel stragies to address the extracellular matrix as an integral part of the immune cell microenvironment in intestinal inflammation. The extracellular matrix not only surrounds immune cells, but also influences them (and vice versa).
To investigate the effects of immune cells on the remodelling of the extracellular matrix in Crohn's disease, SP B06 will investigate in vivo accessible glucosaminoglycans (GAG) within the extracellular matrix. These GAGs characterise processes in intestinal inflammation and in the remodelling of the extracellular matrix. In vivo imaging of mouse models in combination with endoscopy and histology in mice and humans will reveal different composition and distribution patterns of GAG in intestinal inflammation as well as the accumulation of extracellular matrix. In the long term, GAG-related criteria will support the development of non-invasive methods to predict complications in Crohn's disease as well as provide treatment options that target deleterious extracellular matrix, thus providing a rationale for individualised treatment. Using relevant mouse models of intestinal inflammation compared to human disease, SP B06 will address the following programme:
1. characterisation of VSOP distribution patterns in vivo in the healthy gut for correlation of local distribution of GAG and immune cells.
2. confirmation of GAG-specific binding of VSOP in intestinal tissues ex vivo.
3. systematically compare VSOP binding with GAG composition in vivo in inflamed and non-inflamed tissues using mouse models of intestinal inflammation.
4. correlation of intestinal GAG and immune cell distribution with clinical disease status in situ in inflammatory bowel disease.
5. analysis of the inflammation-dependent composition of GAG in the intestinal extracellular matrix in situ.
Publications
- Garczyńska K, Tzschätzsch H, Kühl AA, Morr AS, Lilaj L, Häckel A, Schellenberger E, Berndt N, Holzhütter HG, Braun J, Sack I, Guo J. Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy. Front Physiol. 2020 Nov 23;11:605205. doi: 10.3389/fphys.2020.605205. PMID: 33329058; PMCID: PMC7719759.
- Mikuda N, Schmidt-Ullrich R, Kärgel E, Golusda L, Wolf J, Höpken UE, Scheidereit C, Kühl AA, Kolesnichenko M. Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut. J Pathol. 2020 Jun;251(2):160-174. doi: 10.1002/path.5437. Epub 2020 May 29. PMID: 32222043.
- Golusda L Small particles going big. Phenotype, 35: 16-17, 2020
- Ziegler JF, Böttcher C, Letizia M, Yerinde C, Wu H, Freise I, Rodriguez-Sillke Y, Stoyanova AK, Kreis ME, Asbach P, Kunkel D, Priller J, Anagnostopoulos I, Kühl AA, Miehle K, Stumvoll M, Tran F, Fredrich B, Forster M, Franke A, Bojarski C, Glauben R, Löscher BS, Siegmund B, Weidinger C. Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease. Nat Commun. 2019 Dec 10;10(1):5629. doi: 10.1038/s41467-019-13559-7. PMID: 31822667; PMCID: PMC6904732.
- Albrecht J, Polenz D, Kühl AA, Rogasch JMM, Leder A, Sauer IM, Babos M, Mócsai G, Beindorff N, Steffen IG, Brenner W, Koziolek EJ. Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats. EJNMMI Res. 2019 Feb 22;9(1):21. doi: 10.1186/s13550-019-0489-6. PMID: 30796555; PMCID: PMC6386759.
- Schmidt F, Dahlke K, Batra A, Keye J, Wu H, Friedrich M, Glauben R, Ring C, Loh G, Schaubeck M, Hackl H, Trajanoski Z, Schumann M, Kühl AA, Blaut M, Siegmund B. Microbial Colonization in Adulthood Shapes the Intestinal Macrophage Compartment. J Crohns Colitis. 2019 Sep 19;13(9):1173-1185. doi: 10.1093/ecco-jcc/jjz036. PMID: 30938416.