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Forschung - Research

Welcome

As to our mission as an academic GI center, we are actively searching for a better understanding of disease causation and pathophysiology and novel therapies.

Clinical Research

The GI unit is active in pharmaceutical clinical trials on inflammatory bowel disease, primary sclerosing cholangitis and primary biliary cirrhosis employing several new compounds and liver disease (end-stage liver disease, TIPPS, ascites pump). Endoscopic research focusses on the evaluation and development of novel endoscopic procedures for instance in interventional ultrasound and photodynamic therapy of cholangiocarcinoma.

Grants

The majority of our translational research is supported by competitive third party grants. Agency with currently running grants include:

Hampe lab

more information on CRTD website

Research focus

Genomic and molecular disease mechanisms of gastrointestinal and hepatological disorders (Group leader: Prof. Jochen Hampe, MD)

The research interest in our group is to unravel the molecular pathways that are implicated in the development of gastrointestinal and hepatological disorders. Specifically, our research focuses on systematic, genome-wide approaches in patient material derived from individuals with disorders such as nonalcoholic liver disease, alcoholic liver disease, gallstone disease, inflammatory bowel disease (IBD), diverticulitis and diverticulosis, colorectal cancer, gallbladder and hepatocellular cancer.

GENOME-WIDE ASSOCIATION STUDIES

Studies of genetic risk factors of complex disorders, and specifically, genome-wide association studies (GWAS) have been widely employed in the study of complex disorders. Through close cooperation with German and international hospitals and research centers we have actively recruited large cohorts with complex disorders and use these for the identification of novel susceptibility genes for gallstone disease, alcoholic liver cirrhosis, colonic diverticular disease (diverticulosis, diverticulitis), colorectal cancer, hemochromatosis,  inflammatory bowel disease and sarcoidosis.

For instance, our group has identified the first common risk factor for gallstone disease (ABCG5/8) through a genome-wide association study. This is now the most widely replicated human susceptibility gene for gallstone disease, which has been shown to confer an approximately twofold increase in gallstone risk. This gene codes for a heterodimeric biliary cholesterol transporter. In order to better understand the mechanistic disease effect conferred by ABCG5/8, genetic fine mapping and cellular assays established cholesterol hypersecretion caused by ABCG8-Asp19His amino acid change as the disease causing mechanisms in this disorder. Recently, our group lead the first genome-wide association study in alcoholic liver cirrhosis.

EPIGENETICS OF GI DISORDERS

Epigenetics describes heritable changes in gene expression without changing the DNA-sequence. To date three mechanisms are known to induce epigenetic changes: DNA methylation, histone modification and ncRNA associated gene silencing.

In our group, we focus on changes in DNA methylation in fatty liver disease where we were able to identify NAFLD-specific expression and methylation differences for nine genes coding for key enzymes in intermediate metabolism and insulin/insulin-like signaling. Intra-individual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Postbariatric and NAFLD-specific methylation signatures were clearly distinct both in gene ontology and transcription factor binding site analyses.

We are now extending the analysis to the key transcription factors to identify differentially expressed genes by Chip-Seq analysis and FAIRE-Seq.

DYSREGULATION OF TRANSLATION IN COMPLEX DISEASES

Eukaryotic protein synthesis involves three stages, initiation, elongation and termination, in which initiation is the rate-limiting step. The complex nature and the number of different factors involved in the translation initiation process harbours several mechanisms how protein synthesis can be controlled. These mechanisms can be divided in to two broad categories:

  1. Global up- or downregulation of protein synthesis by changing the phosphorylation state or degradation of initiation factors and
  2. regulation of individual transcripts through the activity of cis-acting elements, like internal ribosomal entry sites (IRES), sequence specific RNA binding proteins, secondary structures influencing scanning kinetics, miRNAs and upstream open reading frames.

We use ribosomal profiling, a method which allows a transcriptome-wide mapping of ribosomes with sub-codon resolution to analyze the complex nature of translational dysregulation in metabolic diseases i.e. non-alcoholic fatty liver disease and different cancer entities.

Team

Scientists

Mario Brosch, PhD

Lab head

Functional genomics

Tel.: 0351 458-4683

Alexander Herrmann

Bioinformatics

Tel.: 0351 458-4146

Stephan Buch, PhD

Genetic association studies

Tel.: 0351 458-4684

Veera Raghavan Thangapandi

Tel.: 0351 458-4684

Vincent Moser

Sophie Nehring

PhD students
Tohid Siddiqui
Technical team

Luise Obermann

Tel.: 0351 458-3757

Sylvia Lehmann

Tel.: 0351 458-3757

Publications

Please find our current publication activity @Google Scholar (link: https://scholar.google.de/citations?user=u9TRfVoAAAAJ&hl=de&oi=ao) and pubmed (link: https://www.ncbi.nlm.nih.gov/pubmed/?term=hampe-j)

Zeissig Lab

Research focus

Immunological mechanisms of inflammation and cancer (Group leader: Prof. Sebastian Zeissig, MD)

Research in the laboratory focuses on the immunological mechanisms of inflammation and tumor development in the intestine and the liver, with particular interest in translational research focusing on monogenic forms of inflammatory bowel disease and the role of inflammation in cancer development.

Microbiota, Inflammation, and Cancer

 Chronic inflammation is a risk factor for the development of cancer and many prominent examples of this association exist in the gastrointestinal tract. This includes associations between inflammatory bowel disease (IBD) and colorectal cancer (CRC), Helicobacter pylori infection and gastric cancer, Hepatitis B and C virus infections and hepatocellular cancer (HCC) as well as non-alcoholic fatty liver disease and HCC. Of note, in many of these examples, inflammation is clinically inapparent, restricted to the respective tissue and dependent on microbial organisms. In line with the principles, we could recently demonstrate that not only sporadic CRCs but also adenomas as their benign predecessor lesions are associated with disruption of the intestinal barrier and translocation of bacteria into host tissue (Peuker,…,Zeissig, Nat. Med. 2016). This is associated with the activation of inflammatory pathways in the intestinal epithelium, such as the pathway of calcineurin and nuclear factor of activated T cells (NFAT), which promotes tumor growth through support of tumor stem cell survival and proliferation. The observation that such pathways are activated early in the process of tumor development suggests that targeting of microbial elements or downstream molecular mediators may provide efficacy in the prevention of tumor development, which is currently being investigated in the lab. Moreover, we explore whether similar pathways are active in other diseases associated with barrier dysfunction, such as liver cirrhosis, and similarly promote tumor development in these organs.

Monogenetic forms of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic intestinal inflammation. In the vast
majority of IBD patients, intestinal inflammation occurs through a complex and incompletely understood interplay of genetic and environmental factors. However, we and others have recently identified forms of mono- or oligogenic forms of IBD, in which one or few genetic defects are sufficient to promote intestinal inflammation (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). Patients with monogenic IBD often present with early-onset disease manifesting during early childhood and exhibit severe and often treatment-refractory intestinal and systemic inflammation. The identification of a genetic etiology in some of these IBD patients not only provided significant insight into the pathophysiology of IBD, but also opened new opportunities for personalized treatment of these patients. This translational research agenda is pursued in close collaboration with the Department of Pediatrics (Prof. Dr. Berner, Prof. Dr. Schütz, Dr. Y.Zeißig) and the Institute of Clinical Molecular Biology (IKMB) Kiel (Prof. Dr. Schreiber, Prof. Dr.
Franke). Genetic screening is offered to patients with early onset and/or familial IBD.

Lipid Antigens in immunity

Natural killer T (NKT) cells are an unconventional subset of T cells that responds to CD1d-restricted presentation of self and foreign lipid antigens and is associated with immediate innate-like effects on NK, T, and B cells thereby shaping and orchestrating immune responses. NKT cells are critical for antimicrobial immunity and genetic defects in lipid antigen presentation are associated with primary immunodeficiency in humans. However, recent studies have revealed that NKT cells are not only contributing to protective immunity but also play central roles in the pathogenesis of chronic inflammatory disorders. Thus, it was shown that ulcerative colitis, an inflammatory bowel disease (IBD), is characterized by NKT cell-dependent intestinal inflammation. Similarly, recent studies have revealed that NKT cells are centrally involved in the pathogenesis of autoimmune and infectious hepatitis.

In our recent work investigating the role of lipid antigens and NKT cells in intestinal and hepatic immunity, we could demonstrate that hepatocytes and intestinal epithelial cells can present lipid antigens via the non-classical MHC class I molecule CD1d to natural killer T cells thus providing the basis for protection from infectious hepatitis as well as intestinal inflammation (Zeissig et al., Nat. Med. 2012; Olszak et al., Nature 2014). Furthermore, this work revealed an essential role of the commensal microbiota and microbiota-derived lipid antigens in the control of homeostasis at mucosal surfaces and demonstrated that primary defects in lipid antigen presentation are associated with immunodeficiency in humans (An et al., Cell 2014; Olszak et al., Science 2012; Zeissig et al., J. Clin. Invest.; Zeissig et al., Nat. Immunol. 2014). Current work in the laboratory is focused on the identification of lipid antigens which link metabolism and immunity in the liver and the intestine (Melum et al., Nat. Immunol. 2019).

Team

Group Leader

Prof. Dr. med. Sebastian Zeissig, M.D.

Principal Investigator

Anne-Kathrin Gerber

Personal assistant

Tel: 0351 458-82354
mailto:Anne-Kathrin.Gerber@tu-dresden.de

Publications

https://www.ncbi.nlm.nih.gov/pubmed/?term=zeissig-s+not+zeissig-sr