Project

Back to overview

Reactive oxygen species (ROS) in inflammation

English title Reactive oxygen species(ROS) in inflammation
Applicant Werner Sabine
Number 137197
Funding scheme ProDoc
Research institution Molekulare Gesundheitswissenschaften Departement Biologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Immunology, Immunopathology
Start/End 01.01.2012 - 31.12.2014
Approved amount 422'964.00
Show all

All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Cancer Research

Keywords (6)

Nrf2; Oxidative Stress; Wound repair; Cancer; Atherosclerosis; Inflammatory bowel disease

Lay Summary (English)

Lead
Lay summary

A large percentage of the population suffers from chronic inflammatory disease and/or inflammation-induced impairments in tissue repair. Furthermore, chronic inflammation is a major risk factor for the development of cancer. Therefore, it is of particular importance to unravel the mechanisms underlying the onset and progression of an inflammatory process and to develop efficient and specific anti-inflammatory strategies. In recent years, the role of oxidative stress in the pathogenesis of inflammatory disease has been increasingly recognized. Reduction in the levels of reactive oxygen species (ROS) has therefore emerged as a promising strategy to reduce inflammation. A key player in the antioxidant defense system is the transcription factor “nuclear factor erythroid derived 2, like 2” (Nrf2), which controls the expression of various ROS-detoxifying enzymes and other antioxidant proteins.

We have developed unique mouse models that allow us to study the consequences of Nrf2 activation or inhibition for tissue homeostasis, repair and disease. These mice will be used to determine the roles of Nrf2 and oxidative stress in the pathogenesis of chronic, non-healing wounds, atherosclerosis, inflammatory bowel disease and cancer. The relevance of our findings for human disease will be studied using samples from patients suffering from these diseases. The project is a collaboration between two basic researchers and a clinical investigator. This will allow us to rapidly transfer our findings into a clinical setting. The graduate students supported through this project will benefit from the experience of the principal investigators in molecular and cellular biology, immunology and clinical medicine. Results obtained in this collaborative project will provide insight into the mechanisms underlying major human diseases as a basis for the development of more efficient therapies.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Cell-specific activation of the Nrf2 antioxidant pathway increases mucosal inflammation in acute but not in chronic colitis
Gerstgrasser Alexandra Melhem H. et al. (2016), Cell-specific activation of the Nrf2 antioxidant pathway increases mucosal inflammation in acute but not in chronic colitis, in Journal of Crohns Colitis, 93, 249-259.
Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans.
Wojtal K.A. Cee. A. et al. (2014), Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans., in Am J Physiol Gastrointest Liver Physiol, 307(7), G673-G688.
Effects of retinoids in mouse models of colitis: benefit or danger to the gastrointestinal tract?
Frey-Wagner I Fischbeck A Cee A Leonardi I Gruber S Becker E Atrott K Lang S Rogler G. (2013), Effects of retinoids in mouse models of colitis: benefit or danger to the gastrointestinal tract?, in Inflamm Bowel Dis, 11, 2356-2365.
Fatty acid–induced mitochondrial uncoupling elicits inflammasome-independent IL-1a and sterile vascular inflammation in atherosclerosis
Freigang SF (2013), Fatty acid–induced mitochondrial uncoupling elicits inflammasome-independent IL-1a and sterile vascular inflammation in atherosclerosis, in Nature Immunology, 14(10), 1045-1053.
Hypoxia induces the expression of transketolase-like 1 in human colorectal cancer.
Bentz S Cee A Endlicher E Wojtal KA Naami A Pesch T Lang S Schubert P Fried M Weber A Coy (2013), Hypoxia induces the expression of transketolase-like 1 in human colorectal cancer., in Digestion, 88(3), 182-192.
Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2
Bretscher Peter, Egger Julian, Shamshiev Abdijapar, Trötzmüller Martin, Köfeler Harald, Carreira Erick, Kopf Manfred, Freigang Stefan, Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2, in EMBO Molecular Medicine, in press.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Daniel Hohl, CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Zurich/ group of Dr. Hans-Dietmar Beer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Jeffrey Johnson, University of Wisconsin United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Georg Bornkamm, Helmholtz Zentrum München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Andere am Prodoc beteiligte Wissenschaftler Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Pfizer Biotherapeutics Research seminar Individual talk Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2 15.12.2014 Boston, United States of America Werner Sabine; Kopf Manfred;
Cutaneous Biology Meeting Talk given at a conference Cytoprotective signaling mechanisms in skin biology and pathology 22.09.2014 Stradbroke Island, Australia Werner Sabine;
6th International Conference on Oxidative Stress in Skin Medicine and Biology Talk given at a conference The bright and the dark sides of the Nrf2 transcription factor in the skin 27.08.2014 Andros, Greece Werner Sabine;
Seminar at the University of Plymouth Individual talk Cytoprotective Signaling Pathways in Tissue Repair and Cancer 15.07.2014 Plymouth, Great Britain and Northern Ireland Werner Sabine;
13th Clinical Research day Poster Tissue specific overexpression of Nrf2 worsens acute but not chronic intestinal inflammation 17.06.2014 Zurich, Switzerland Cee Alexandra; Rogler Gerhard;
Meeting on oncogenic pathways and anti-tumor responses Talk given at a conference Cytoprotective signaling pathways in tissue repair and cancer 23.04.2014 Athens, Greece Werner Sabine;
World Immune Regulation Meeting VIII Individual talk Thioredoxin reductase-1 is essential for expansion of activated T cells and anti-viral immunity 19.03.2014 Davos, Switzerland Kopf Manfred; Heer Sebastian;
Distinguished Scientist Lecture Individual talk Cytoprotective Signaling Pathways in Tissue Repair and Cancer 21.01.2014 Houston, United States of America Werner Sabine;
Seminar at the Institute of Biochemistry, University of Lausanne Individual talk Cytoprotective signaling pathways in tissue repair and cancer 21.11.2013 Lausanne, Switzerland Werner Sabine;
New Embo Member Meeting Talk given at a conference Parallels between wound healing and cancer 18.10.2013 Heidelberg, Germany Werner Sabine;
United European Gastroenterology Week Talk given at a conference Tagretting the Epithelial Barrier 13.10.2013 Berlin, Germany Rogler Gerhard;
Seminar at the University of Alicante, Spain Individual talk Parallels between wound healing and cancer 04.10.2013 Alicante, Spain Werner Sabine;
SIAF Seminar Individual talk Alveolar Macrophages: Development and Function in Respiratory Viral Infection 23.09.2013 Davos, Switzerland Kopf Manfred;
Annual Meeting of SGG, SGVC and SASL Talk given at a conference Tissue specific overexpression of the transcription factor Nrf2 increases mucosal inflammation in an acute DSS mode 13.09.2013 Basel, Switzerland Cee Alexandra;
Annual Meeting of SGG, SGVC and SASL. Poster Tissue specific overexpression of the transcription factor Nrf2 increases mucosal inflammation in an acute DSS model 11.09.2013 Basel, Switzerland Joshi Natasha; Werner Sabine;
Seminar, University of Ulm, Germany Individual talk Cytoprotective signaling pathways in tissue repair and cancer 16.07.2013 Ulm, Germany Werner Sabine;
Advanced Course in Clinical Immunology Talk given at a conference INNOVATIVE THERAPIES based on IMMUNOLOGY in Gastroenterology 02.07.2013 Cordeliers Research Center, Sorbonne, Paris, France Rogler Gerhard;
4th Lübeck Regenerative Medicine Symposium Talk given at a conference Parallels between wound healing and cancer 27.06.2013 Lübeck, Germany Werner Sabine;
Gordon Research Conference on Tissue Repair and Regeneration Talk given at a conference Cytoprotective Signaling pathways in wound healing and cancer 16.06.2013 New London, United States of America Werner Sabine;
Falk Seminar Ludwigshafen Talk given at a conference Ätiopathogenese von CED 15.06.2013 Ludwigshafen, Germany Rogler Gerhard;
IOIBD Annual Meeting Talk given at a conference Fibrosis and fistula formation in IBD: two sides of the same medal 19.04.2013 New York, United States of America Rogler Gerhard;
Wolfsberg meeting Talk given at a conference Nrf2 targets promote inflammasome activation 03.04.2013 Wolfsberg, Switzerland Heer Sebastian;
AEK International Cancer Congress Talk given at a conference Parallels between wound healing and cancer 22.03.2013 Heidelberg, Germany Werner Sabine;
World Immune Regulation meeting Talk given at a conference Thioredoxin reductase-1 is essential for expansion of activated T cells and anti-viral immunity 13.03.2013 Davos, Switzerland Kopf Manfred; Heer Sebastian;
Biochemical Society Conference: Nrf2 signalling in health and disease Talk given at a conference Tissue specific overexpression of the transcription factor Nrf2 increases mucosal inflammation upon dextran sulphate sodium treatment 11.12.2012 London, Great Britain and Northern Ireland Cee Alexandra;
7th Symposium of the ZIHP Talk given at a conference Role of tissue specific overexpression of the transcription factor Nrf2 in mucosal inflammation 24.08.2012 Zurich, Switzerland Cee Alexandra;
Digestive disease week, San Diego Poster Tissue specific overexpression of the transcription factor Nrf2 increases mucosal inflammation upon dextran sulphatesodium treatment 24.05.2012 San Diego, United States of America Rogler Gerhard; Cee Alexandra;
11th Clinical Research day, Zurich Poster Role of tissue specific overexpression of the transcription factor Nrf2 in mucosal inflammation 20.04.2012 Zürich, Switzerland Cee Alexandra; Rogler Gerhard;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Verteidigung bei Gefahr: Das Immunsystem German-speaking Switzerland 2013

Awards

Title Year
John H. Blaffer Distinguished Lecture, MD Anderson Cancer Center, Houston, Texas 2014
Ehrenpreis der Schweizer Gastroenterologischen Gesellschaft SGG 2013
Ethicon Travel Award, Annual Meeting of SGG, SGVC and SASL 2013 (September 2013) 2013
Honorary Membership of the South African Gastroenterology Society 2013
AGA-Horizon Pharma Student Abstract Prize. American Gastroenterological Association (AGA) Research F 2012
EMBO membership 2012
IOIBD Membership (International Organitzation of IBD Research 2012

Abstract

A large percentage of the population suffers from chronic inflammatory disease and/or inflammation-induced impairments in tissue repair. Furthermore, chronic inflammation is a major risk factor for the development of cancer. Therefore, it is of major importance to unravel the mechanisms underlying the onset and progression of an inflammatory process and to develop efficient and specific anti-inflammatory strategies. In recent years, the role of oxidative stress in the pathogenesis of inflammatory disease has been increasingly recognized. Reduction in the levels of reactive oxygen species (ROS) has therefore emerged as a promising strategy to reduce inflammation. A key player in the antioxidant defense system is the transcription factor “nuclear factor erythroid derived 2, like 2” (Nrf2), which controls the expression of various ROS-detoxifying enzymes and other antioxidant proteins. Loss of Nrf2 in mice enhances the susceptibility to various toxins and promotes carcinogenesis. Furthermore, several recent reports suggest that Nrf2 deficiency also promotes inflammatory processes due to reduced ROS detoxification and subsequent development of oxidative stress. On the other hand, pro-inflammatory functions of Nrf2 have also been described, and activating mutations in the NRF2 gene or inactivating mutations in the gene encoding its inhibitor KEAP1 were found in various cancers in humans, resulting in enhanced tumor malignancy. The goal of the proposed project is to unravel the role of Nrf2 in inflammation using in vitro studies, functional studies in mice as well as expression studies using biopsies from patients with inflammatory disease and cancer. Specifically, we will determine the roles of Nrf2 in wound healing and skin carcinogenesis (Werner group), atherosclerosis (Kopf group), and inflammatory bowel disease and colon cancer (Rogler group). Mouse models to study the pathogenesis of these disorders are established in our groups and will be used for this purpose. In particular, the consequences of loss, inactivation or activation of Nrf2 in granulocytes and macrophages for the development and progression of these diseases shall be determined. To achieve these goals, we will share recently developed genetically modified mice with gain- or loss-of-function of Nrf2 as well as reagents and technologies that have been generated/established in our laboratories. By bringing our groups together, we will benefit from the individual expertise of each group in cell and molecular biology, immunology and/or experimental and clinical medicine. The inclusion of a group with clinical expertise will help to transfer our results into the clinical practice. The PhD students involved in this Prodoc project will be jointly supervised by all principal investigators involved in this project. This will promote a strong interaction between the students and their supervisors, and will allow the students to benefit from the knowledge/expertise of all groups.The proposed studies are likely to provide insight into the function and mechanisms of action of Nrf2 in myeloid cells and unravel pro- and anti-inflammatory functions of this transcription factor under different physiological and pathological conditions. Furthermore, they are expected to extend our knowledge on the pathogenesis of atherosclerosis, inflammatory bowel disease, chronic skin ulcers and inflammation-induced cancer. This will be a prerequisite for the development of novel and more specific therapies for the treatment of these major and frequently life-threatening human diseases. Finally, this collaborative project will strongly contribute to the training of young investigators in cell biology, immunology as well as experimental and clinical medicine.
-