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