Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are characterized by chronic relapsing inflammatory processes in the gastrointestinal tract. Due to the progressive and destructive nature and the increasing frequency of both disorders, new insights into their pathophysiology as a rational basis for innovative therapeutic approaches are urgently needed. However, the etiological background of these diseases remains poorly understood and still holds many open questions, particularly with regard to the in-depth understanding of local cell – cell interactions. As a joined initiative between Erlangen and Berlin, the TRR 241 will integrate aspects and knowledge about mucosal immune regulation and epithelial barrier defense into a new concept highlighting the role of immune-epithelial communication in the pathogenesis of IBD.
The driving hypothesis of our initiative is that a dysregulated signal exchange between the epithelium and immune cells and the consequences thereof contribute to the pathogenesis of IBD and we are confident that our specialized and multi-modal approaches to investigate these processes will give rise to unique and innovative strategies to counter IBD. This CRC initiative brings together a group of highly experienced gastroenterologists, immunologists and cellular and molecular biologists with expertise in experimental, translational and clinically-oriented research to ensure the realization of the aims defined in this proposal. The research program of this CRC has been designed to advance not only basic concepts of IBD development, but also to provide an outstanding platform for translational studies and pre-clinical and clinical testing. Our research efforts are built on a solid fundament of state-of-the-art technology platforms, such as in vivo imaging, next generation sequencing, intestinal organoid technology and molecular imaging present in both Erlangen and Berlin.
In the frame of a newly established interdisciplinary Research Training Group (iRTG) from the Medical Faculty of the Friedrich-Alexander-University of Erlangen-Nürnberg (FAU) and of the Charité Universitätsmedizin Berlin we offer several PhD Positions.
- Master’s Degree (or equivalent) in Life Science and excellent academic performance
- Practical and theoretic experience in the field of molecular biology, immunology or cell biology
- Very good knowledge of English
- High level of motivation, ambition and scientific interest.
The applicant should provide the following admission documents in English:
- Motivation letter
- Signed Curriculum Vitae
- Copies of earned University degrees and prior undergraduate and graduate transcripts
- References: Contact information of two University professors and possibly two letters of recommendation
The documents are to be sent in digital form (one pdf document) under the reference “iRTG-TR 241-PhD application” to Rita.Raschke@uk-erlangen.de and Birgit.Roeders@charite.de. For further information, please write an email.
Innate modules of intestinal epithelial cell protection in inflammatory bowel diseases.
It is well recognized that innate and adaptive immunity are inappropriately activated in inflammatory bowel diseases (IBD) and promote tissue destruction. Innate mechanisms protecting intestinal epithelial cells have been recently identified but are less well understood. We will dissect the mechanisms leading to IL-22-mediated epithelial protection, granuloma formation and granuloma-mediated epithelial barrier repair program in the context of IBD. These studies may lead us to identify innate immune targets for the treatment of IBD.
Mechanisms linking IFN-mediated mixed lineage kinase domain-like protein activation with intestinal inflammation.
Despite the fact that interferons (IFNs) act at mucosal surfaces, limited knowledge is available on the molecular mechanism of their mucosal functions. Our unpublished data suggest a major contribution of IFN-induced programmed necrosis to the pathogenesis of intestinal inflammation. Accordingly, IFNs promote non-apoptotic epithelial cell death, upregulation of mixed lineage kinase domain-like protein and loss of immune homeostasis. The central question of this project is if and by which pathways epithelial IFN-regulated necrosis contributes to intestinal inflammation. We aim to discover novel functions of IFNs in immune-epithelial communication that could be targeted for future therapeutic intervention.
Mucosal type 2 immunity as regulator of epithelial cell functions in inflammatory bowel diseases.
Central mediators of prototypical type 2 responses such as IL-33 are upregulated in the mucosa of patients with IBD, but how type 2 responses may drive pathological features of IBD or vitally contribute to the protective tissue response to damage still remains ill-defined. In this proposal, we aim to comprehensively address, how IL-33 production and signaling controls mutual interactions between the immune, stromal and epithelial cell compartments in vitro and in vivo. These insights together with the analysis of large cohorts of IBD patients and their stratification will be used to predict, whether targeting of type 2 molecules may be a strategy for personalized medicine in IBD.
Microbiota - TLR4 - TNFα axis in control of epithelial tissue functions in IBD.
Intestinal epithelial cell (IEC) homeostasis during IBD can be facilitated by increased expression of cytokines, such as tumor necrosis factor-α (TNF-α), and by toll-like receptor (TLR) ligands derived from microbiota. However, the mechanisms of immune system-mediated tissue repair in IBD remain elusive. We have previously found that anti-TNF-α therapy induced IEC restitution is mediated by IL 22-driven IEC proliferation. Next, we revealed that antibiotic-induced changes in microbiota distinctly contributed to the restoration of the epithelial barrier via a TLR4-dependent mechanism. Thus, we aim to dissect the significance of the microbiota-TLR4-TNFα axis for IEC layer restoration during IBD.
Oncostatin M - a novel cytokine in inflammatory bowel diseases pathogenesis.
Oncostatin M (OSM) is a highly expressed cytokine in IBD and high pretreatment expression is strongly associated with failure of anti-TNF-a therapy. OSM promotes intestinal inflammatory pathology and genetic deletion or pharmacological blockade of OSM significantly attenuates colitis in mice. Our hypothesis is that OSM acts as an inflammatory amplifier and driver of disease chronicity by impacting on both stromal and epithelial cells. We believe that a better understanding of OSM-OSMR pathway in intestinal biology could facilitate the development of novel therapeutic strategies targeting this pathway in IBD.
Inflammation-induced intestinal vascular barrier dysfunctions and their impact on the immune-epithelial crosstalk in inflammatory bowel diseases.
The intestinal vascular system exerts a critical barrier function during inflammatory bowel diseases (IBD). IFN-gamma is an important pathogenesis factor in IBD with potent vascular-directed activities. The principal aim of the project is to elucidate the molecular mechanisms by which the activation of vascular endothelial cells by IFN-gamma impairs vascular barrier functions and disturbs the immune – epithelial cell crosstalk in the course of IBD pathogenesis. On the long term, we aim to identify novel molecular mechanisms of IFN-gamma-induced gut-vascular barrier dysfunction, which may be exploited as new targets of therapy in IBD.
Regulation and function of prenylation within intestinal epithelial cells in the context of inflammation.
Our project aims on an improved understanding of the regulation of prenylation within intestinal epithelial cells (IECs) and its function in epithelial integrity in the context of inflammatory bowel diseases (IBD). We will investigate molecular mechanisms regulating epithelial prenylation in order to experimentally validate our key hypothesis that the inflammation-dependent alteration of prenylation in IECs is regulated via IEC-intrinsic (prenyltransferase activity and availability of isoprenoids), but also via IEC-extrinsic mechanisms (immune cell- or microbiota-derived mediators). Finally, we intend to translate our findings in innovative biomarker and therapy strategies in IBD.
Molecular and functional studies on the crosstalk between induced IELs and IECs in intestinal homeostasis and inflammation.
Induced intra-epithelial lymphocytes (iIELs) are widely distributed within the intestinal epithelial cell (IEC) layer. However, differentiation and function of iIELs in healthy individuals and their role within the pathogenesis of inflammatory bowel diseases (IBD) await to be fully elucidated. We found that selected deficiencies within the conventional DC (cDC1) compartment result in distinct iIEL pool alterations. Hence, employing cDC1-targeted mice as iIEL deficiency model systems we seek to study the molecular mechanisms and functional consequences of the iIEL-IEC crosstalk during intestinal homeostasis and inflammation.
Mesenteric fat - an immunological barrier in Crohn's disease?
Creeping fat represents a disease characterizing finding in Crohn's disease but its impact on intestinal inflammation and epithelial barrier function is unknown. The present project aims to define how intestinal barrier defects shape the homeostasis of mesenteric fat, how these alterations confer to an alternative intestinal barrier and how creeping fat modulates epithelial resistance as well as intestinal immune cell composition and immunity. A fat-depleting mouse model will serve to answer these questions and the data will subsequently be correlated to results obtained from a Crohn's disease patient cohort.
Signals mediating crosstalk of intestinal epithelial cells with innate lymphoid cells in inflammatory bowel diseases.
Innate lymphoid cells (ILCs) are major regulator of intestinal epithelial cell (IEC) homeostasis and play a dual role in intestinal inflammation. However the mechanisms underlying this phenomenon remain unclear. We postulate that distinct IEC signals can shape ILC effector functions, thereby differentially impacting on epithelium responses and intestinal inflammation. Central focus of this project will be the characterization of signals governing the ILC-IEC crosstalk during homeostasis and inflammation. Identification and manipulation of such pathways will be used to promote IEC regeneration and protective functions, while dampening pathogenic circuits involved in inflammatory bowel disease.
The intestinal epithelial cells in the dialogue between microbiota and the immune system.
The intestinal microbiota can determine functional differentiation of mucosal T helper (Th) cells, licensing them to promote or protect from intestinal inflammation. The central aim of this project is to determine the molecular crosstalk between distinct pro- and anti-inflammatory bacteria of the microbiota and the mucosal Th cells, and the role the intestinal epithelial cells (IEC) play in this. We will identify the bacteria licensing T-bet-deficient Th cells to induce colitis and determine how these bacteria affect the IEC barrier. Furthermore, we will determine how bacteria of the genus Anaeroplasma pass or affect the IEC barrier, induce TGF-β in mucosal Th cells and potentially ameliorate colitis.
The emergency barrier function of neutrophil extracellular traps and their interaction with the intestinal epithelium.
Neutrophil extracellular traps (NETs) instigate plasmatic coagulation and form emergency barriers on mucosal wounds with antimicrobial, yet also strong cytotoxic properties. We now identified that NETs take part in guiding mucosal healing responses. Restituting epithelia protect themselves from NET-borne cytotoxic mediators. We will focus on these protective mechanisms used by specialized epithelial cells and envision future therapies directed at NET-epithelial imbalances to support mucosal healing in patients suffering from IBD.
Neuropeptides and TRP channels as effectors in colonic epithelial and immune cell function in IBD.
Recent data suggests an emerging role for peptidergic neurons in the pathogenesis of intestinal inflammation. Neuropeptide release is controlled by transient receptor potential (TRP) channels. Own data suggest a previously unknown role of extra-neuronal TRP channel expression in intestinal immune and epithelial cells as well, indicating a complex neuro-immune-epithelial signaling network in the gut. The central topic of this project is to understand how enteric neurons via secretion of neuropeptides orchestrate intestinal homeostasis and how TRP activation regulates intestinal mucosal immunity and epithelial cell function in addition.
Interplay of the impaired tight junction and the subjacent immune cells in IBD.
Impairment of the tight junction (TJ) is linked to enhanced luminal antigen uptake supporting inflammatory processes in IBD. We hypothesize that especially the tricellular tight junction (tTJ) is crucially involved in this and in immune cell activation. Thus, we will analyze effects and interactions between the (t)TJ and the immune cells beyond during development of intestinal inflammation. Elucidation of regulatory pathways beyond will identify possible targets of intervention, which then will be used for strategies stabilizing the (t)TJ barrier preventing antigen entry and perpetuation of inflammation in order to protect against development of IBD.
Identification and functional characterization of human microbiota-specific regulatory T cells.
Foxp3+ regulatory T cells (Tregs) are key players for the maintenance of tolerance against self and harmless exogenous antigens, such as the intestinal microbiota. Microbiota-specific Tregs therefore represent powerful targets for novel and specific therapies in inflammatory bowel disease (IBD). We have developed technologies to identify and characterize human microbiota-specific Tregs. We will screen for important Treg targets, isolate and expand Tregs with relevant specificities and analyze their functional characteristics as a basis for development of tailor-made Treg for IBD therapy.
Determining function and dysfunction of the intestinal epithelium using advanced label-free imaging techniques.
Advanced label-free optical technologies such as multiphoton microscopy and Raman spectroscopy hold great potential for a characterization of mucosal inflammation in vivo. Using these approaches, we will evaluate optical properties of epithelial barrier function and dysfunction as well as consequences of epithelial barrier defects including immune cell infiltration and bacterial translocation in preclinical colitis models ex vivo and in vivo. Based on these studies, project C01 will further develop advanced optical technologies for the in vivo evaluation of mucosal inflammation in human IBD.
In vivo endoscopic molecular imaging to predict response to biological therapies in ulcerative colitis.
We will test clinically approved antibodies targeting cytokine signaling or integrin-based homing of immune cells in the gut for their potential to allow endoscopic molecular in vivo imaging in ulcerative colitis patients. The GMP conform fluorescent antibodies will be applied to the inflamed mucosa of ulcerative colitis patients during endoscopic confocal laser endomicroscopy to decipher the molecular signature driving mucosal inflammation in individual patients. Such in vivo mapping of relevant inflammatory signaling pathways may allow the selection of the ideally suited neutralizing antibody for subsequent therapy and will thus open new avenues for personalized medicine in ulcerative colitis.
Transcranial direct current stimulation for chronic, IBD-associated abdominal pain and the relation of pain perception and the intestinal epithelial barrier.
A clinical phase-III-study was designed to test tDCS (transcranial direct current stimulation) on its analgesic effects in IBD-patients with chronic abdominal pain. fMRI scans will be performed in these patients in order to investigate changes in the central nervous system. Based on preliminary data we propose a brain - gut interaction. This will be evaluated by analyzing the effects of tDCS on the intestinal epithelial barrier. To reveal the mechanisms involved, we included a murine model of intestinal inflammation-associated pain where the effects of tDCS on the enteric nervous system, intestinal barrier, neurotransmitters as well as perineural immune cells will be investigated.
A phase II multi-center clinical trial to study efficacy and in vivo trafficking of autologous adoptively transferred ex vivo expanded regulatory T cells in patients with ulcerative colitis.
Adoptive transfer of regulatory T cells (Treg) has successfully been used for blockade of experimental colitis in vivo, but their usage for treatment of patients with ulcerative colitis (UC) remains poorly studied. Gut homing and effects on the gut epithelium of these Treg are detrimental to suppress gut-specific inflammation. In this project, we will further define the molecular mechanisms of mucosal trafficking and retention of Treg in UC. We will combine the clinical assessment of our current GMP-approved Treg in a phase II clinical trial with in depth studies on their gut-homing potential. These studies will result in further refinement of the current GMP-approved Treg product in future studies.
The IBDome project will develop a web-accessible database that integrates large-scale omic-datasets from IBD patients with corresponding clinical disease status. The database will include two types of data: 1) data from deep profiling using cutting-edge technologies on a specified exemplary patient cohort including controls provided by four preselected projects of the consortium, and 2) data from broad profiling of a large number of samples from the existing tissue banks in Erlangen and Berlin.
The structured educational program provided by the iRTG will qualify the PhD researchers of the TRR 241 for a future scientific career at the interface between clinical and biological research.
The Project will cover all administrative tasks of the TRR241
Prof. Dr. Christoph Becker
Prof. Dr. Britta Siegmund
Charité – Universitätsmedizin Berlin