Disorders in steroid production make the organism more likely to develop inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease. The research team led by Prof. Dr. Thomas Brunner at the University of Konstanz has found out that intestinal epithelial cells are able to synthesise anti-inflammatory steroids (glucocorticoids) following immunological stress, which makes a considerable contribution to the maintenance of local immune homoeostasis. The researcher plans to use his findings in the field of extra-adrenal glucocorticoid synthesis to develop a therapeutic approach for the treatment of inflammatory bowel diseases. A major research focus centres on programmed cell death (apoptosis) in cancer and autoimmune diseases.
Bowel diseases mainly affect the epithelial mucus lining in the colon and small intestine, resulting in inflammatory abscesses that bleed easily. The causes of such bowel diseases are still largely unknown. At the Department of Biochemical Pharmacology at the University of Konstanz, Prof. Dr. Thomas Brunner focuses on extra-adrenal glucocorticoid synthesis and its impact on the development of inflammatory bowel diseases. His research group was the first to find out that intestinal epithelial cells are able to synthesise glucocorticoids following immunological stress and that disorders of steroid production make the organism more sensitive to the development of inflammatory bowel diseases. "There are already concrete translational approaches in this field that are being discussed with pharmaceutical companies," said Thomas Brunner.
Glucocorticoid synthesis in the adrenal gland is mainly regulated by the transcription factor SF1, which, however, is not expressed in the intestines. The researchers from Konstanz use different approaches, including luciferase reporters, transfection and RNA interference, to gain insights into the complex processes of glucocorticoid synthesis. Animal experiments are used to investigate complex processes in whole organs. "Our studies have shown that SF1 is functionally replaced by the transcription factor and nuclear receptor LRH-1. We also found that the reduction of its expression in the intestinal epithelium leads to a higher sensitivity and more likelihood of developing inflammatory bowel diseases," explains Prof. Brunner. LRH-1 mainly controls the synthesis of glucocorticoids by way of the transcriptional regulation of glucocorticoid-synthesising enzymes. Locally produced glucocorticoids control intestinal immune cells by inhibiting cell death and their effector functions.
In the next step, the researchers will focus on the activation of the transcription factor LRH-1 through ligands and other signalling pathways in order to stimulate local glucocorticoid synthesis. The researchers thus hope to be able to restore self-regulation in patients suffering from inflammatory bowel diseases such as Crohn's disease or chronic colon inflammation.
Another of Prof. Thomas Brunner's research foci is apoptosis, i.e. programmed cell death that leads to the removal of cells that are no longer required or that hinder the development or survival of the organism. Disorders in apoptosis might lead to diseases such as cancer or autoimmune diseases that could cause a great deal of damage. Prof. Brunner is trying to elucidate the cause of such disorders by inducing cell death in tumour cells and primary T-lymphocytes and tissue cells in vitro and in vivo as well as using biochemical, cell biological and molecular biological methods. These investigations are expected to lead to drug therapies that specifically target cancer cells and make them undergo apoptosis. "The biggest problem for us is how to make the treatment as selective as possible. The drugs need to induce programmed cell death in tumours whilst sparing normal tissue cells," said the biologist. Since the signalling pathways of tumours and normal cells only differ minimally, medicinal therapy might often cause considerable adverse side effects.
The scientists' field of research focuses on concrete human diseases, which is why the translation of the findings into medical diagnostics and therapy are an integral part of their research. "The excellent training of graduate and doctoral students in our disease-related areas contributes to the efficient transfer of our concepts and ideas into pharmaceutical research and to the development of therapies," explains Prof. Brunner who attaches great importance to interdisciplinary cooperation with other research institutions. "We work with a broad range of different research groups, both at the University of Konstanz and at other international institutions, in the fields of immunology, pharmacology, cell biology, oncology and endocrinology," said Brunner. The interdisciplinary cooperation has already proved of great value in the investigation of extra-adrenal glucocorticoid synthesis.
Prof. Dr. Thomas Brunner did his doctorate in Berne (Switzerland) where he concentrated on the regulation of inflammatory diseases. As post-doctoral researcher at the "La Jolla Institute for Allergy and Immunology", Brunner was introduced to research on apoptotic cell death. He subsequently moved to the University of Berne where his independent research group carried out research on cell death and glucocorticoids and their impact on the regulation of inflammatory diseases. Brunner has been professor of biochemical pharmacology at the University of Konstanz since October 2010.
Prof. Dr. Thomas Brunner
University of Konstanz
Tel.: +49 7531 88-5370