Anke Jansen MD student Schwerpunkte der Arbeitsgruppe / Research focus

Transcription

1 AG Sellge Arbeitsgruppe / Group Gernot Sellge group leader gsellge@ukaachen.de Ana Mandic PhD student amandic@ukaachen.de Eveline Bennek PhD student ebennek@ukaachen.de Silvia Roubrocks lab technician sroubrocks@ukaachen.de Julien Verdier Post-doctoral scientist jverdier@ukaachen.de Lisa Frehn lisa.frehn@rwthaachen.de Anke Jansen anke.jansen@rwthaachen.de Teresa Langen teresa.langen@rwthaachen.de Schwerpunkte der Arbeitsgruppe / Research focus 1. Signalling pathways in inflammatory bowel disease (IBD) Staff: Ana Mandic, Julien Verdier, Silvia Roubrocks Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal system of unknown aetiology that affects patients of all age groups including children. Intracellular signalling pathways such the NF-κB and MAP-kinase pathways are master regulators of inflammation but also of cellular development and survival. A balanced activation of these pathways seems to be important to maintain homeostasis in the gastrointestinal tract and experimental studies and data from patients suggest that NF-κB and MAP-kinase pathways are dysregulated in the course of IBD. Using animal and cell culture models, we are currently studying the role of C-June N-terminal kinases (JNK) in IBD. Furthermore, we are part of a collaborative research initiative that aims at revealing oscillating biological processes such as the NF-κB pathway associated with IBD by applying a systems medicine approach. The international SysmedIBD consortium led by Werner Müller, Manchester consists of mathematicians, systems biologists, geneticists, molecular and cellular biologists, immunologists and clinicians. The objective of the project in

2 Aachen together with clinical centres at the Universities of Maastricht and Liverpool is to link the basic research, mathematical modelling and discovery of small molecules back to the clinical situation of IBD patients. The aim of these projects is to define new treatment targets and biomarkers that may predict the disease s course and the outcome of treatment.. Deficiency of JNK 1 and 2 causes enhanced caspase 3 activation (brown colour) as a marker for apoptosis in murine intestinal epithelial cells during experimentally induced colitis. WT, wild type; JNK1 IEC, JNK1- deficiency in intestinal epithelial cells; JNK2-/-, complete knock-out for JNK2; JNK1 IEC JNK2, double knockout. 2. Development of glycan-functionalized microgels for specific binding of Clostridium difficile toxins Staff: Silvia Roubrocks, Ana Mandic The project funded by the SFB 985 combines expertise from polymer chemistry (Alexander Kühne, DWI, RWTH Aachen), glycobiotechnology (Lothar Elling, Helmholtz-Institute, RWTH Aachen), and biomedical science (our group, external collaborator Ralf Gerhard, MH Hannover) with the goal of developing a novel non-antibiotic therapy for Clostridium difficile (C. difficile) associated disease (CDAD), a disorder that represents a worldwide increasing health problem. C. difficile produces two toxins, called toxin A (TcdA) and toxin B (TcdB), which cause tissue disruption and inflammation in the gastrointestinal tract leading to clinical symptoms ranging from mild diarrhea to life-threatening conditions like fulminant pseudomembranous colitis or toxic megacolon. We are developing glycan functionalized and charged microgels with a core-shell structure that specifically bind TcdA and TcdB, in order to eliminate TcdA/B from the gastrointestinal tract and improve current CDAD therapy. TcdA/B will be scavenged by microgels as a result of non-specific electrostatic interactions between both toxins and charged groups on the microgel, and specific interactions between the sugar binding domains of TcdA/B and glycans. Microgels are tested in vitro and in vivo in cell culture and a murine CDAD model. Microgels capable of removing TcdA/B from the GI tract are expected to have the potential for a novel therapeutic approach to reduce CDAD induced morbidity and mortality.

3 HT-20 cells were exposed to Clostridium difficile toxin A and B (TcdA/B) for 5 hours cells. Cell rounding was quantified by counting. 3. Recognition of intestinal food and microbial antigens by the adaptive immune system during homeostasis and inflammation Staff: Eveline Bennek, Lisa Frehn, Anke Jansen, Teresa Langen Collaborators: Thomas Kufer, Uniklinik Köln; IngaBenz / Alexander Schmidt, Uni Münster; Claude Parsot / Phillippe Sansonetti, Institut Pasteur, Paris; Gerda Wurpts / Stefani Röseler, Hautklinik, UKA The immune system of the gastrointestinal tract in confronted with an enormous amount of potentially harmful antigens derived from food and the microbiotic flora. During homeostasis intestinal antigens trigger mainly a tolerogenic immune response, whereas in the course of an infection with a pathogen proinflammatory effector responses are induced and required for pathogen clearance. Dysregulated immune responses to the microbiotic flora and food are found in patients with inflammatory bowel disease and food allergy, respectively. We are aiming to understand the differential potency of food antigens that are present as soluble proteins and microbial-derived antigens that are associated with proinflammatory molecules such as bacterial cell wall components (e.g. LPS or peptidoglycans) to induce T and B cell responses in the gastrointestinal tract. To this end, we are analysing serum and stool antibody levels against food and floral antigens in IBD and food allergy patients as well as in controls. Furthermore, we are using animal models to study the intestinal immune response to model antigens either in soluble form or expressed in different compartments of a non-pathogenic Escherichia coli during homeostasis and intestinal inflammation. The objective of the project is to further understand the mechanisms that underlie tolerance versus effector responses induced by luminal antigens and, thus, to define new therapeutic strategies for IBD and food allergy.

4 Serum IgG antibodies against food and microbial antigens in patients with Crohn s Disease (CD), Ulcerative Colitis (UC), and controls (Con). Expression of ovalbumin in different compartments of E. coli. Anti-ovalbumin antobodies cannont cross the bacterial cell wall. Förderung / Funding The group is currently funded by Deutschen Forschungsgemeinschaft: Einzelförderung Deutschen Forschungsgemeinschaft: SFB 985 Functional Microgels and Microgel Systems START-Programm der Medizinischen Fakultät der RWTH-Aachen Europen Commision (FP7): Systems medicine of chronic inflammatory bowel disease Veröffentlichungen / Publications* Kontakt / Contact information:

5 Dr. med. Gernot Sellge, PhD Tel.: ++49 (0)