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Forschung / Research

Übersicht zu Forschungsarbeiten
Bild von Immunfluoreszenzmikroskop
Foto: Maria Schwarz

Research Projects

1. Interactions of essential trace elements in healthy and diseased elderly (TraceAge)

The homeostasis of trace elements (TE) is affected by nutritional intake, sex, age, and health status. However, interactions of TE under physiological and pathophysiological conditions are poorly characterized. Here we aim to characterize the TE status in women and men of different age (EPIC-Potsdam cohort). To this end, we will measure the TE profiles (Se, Cu, Zn, Mn, Fe, I) from serum along with novel and established biomarkers of the TE status. These data will be combined to establish age- and sex-specific TE fingerprints of German elderly, and help to identify genetic and environmental modifiers. In order to test the relevance of such TE fingerprints, patients with cardiovascular disease during hospitalized rehabilitation (TEhab cohort) will be studied as a paradigm of severe disease with strong changes in mobility and nutrition. To get further mechanistic insights we will study TE profiles and their functional interactions in different tissues from young and old male and female mice under TE-replete and TE-poor conditions. Treatments with TE combinations in mice and C. elegans will identify TE effects on aging, cellular signaling, neurodegeneration, and immune response as well as interactions with drugs and thyroid hormone metabolism. Our results will broaden the understanding of the importance of TE in health and disease. This will provide a basis for better care and future intervention studies to improve the TE status of seniors and to better protect them from degeneration and age-related diseases.

TraceAge-Homepage: https://www.uni-potsdam.de/traceage/

Logo TraceAge Logo TraceAge Foto: TraceAge
Project Kipp (First funding period): Interactions of trace element profiles with Nrf2 signaling in mice

We hypothesize that age-specific trace element (TE) profiles are modulating the activity of the redox-sensitive transcription factor Nrf2. Vice versa, Nrf2 is supposed to regulate the systemic TE status by changing the expression of TE transport and binding proteins, e.g., in the intestine. To address these points, we aim to conduct feeding experiments in young and old mice fed with adequate or suboptimal amounts of six essential TE, including Cu, Fe, I, Mn, Se, and Zn. In addition, we will establish ‘young-adapted’ and ‘old-adapted’ TE diets, which will mimic the TE status of young and old human EPIC participants. A great advantage over human studies is the availability of murine tissue samples, in which effects of different TE diets will be studied in close collaboration with all experimental groups of the Research Unit. We will focus on the liver and the intestine. Using these tissues, we will correlate TE profiles, TE biomarkers, TE-specific binding proteins, and aging markers with Nrf2 pathway activity. We aim to identify new Nrf2-dependent genes relevant for TE homeostasis and intestinal TE absorp­tion both in young and old mice. To identify the Nrf2-modulated part of TE effects, Nrf2 knockout (KO) mice will be studied in parallel. Potential differences between young and old WT and Nrf2-KO mice may provide an explanation for age-specific TE profiles.

Key publications:

Wolfram T, Schwarz M, Reuß M, Lossow K, Ost M, Klaus S, Schwerdtle T, Kipp AP (2020). N-acetylcysteine as modulator of the essential trace elements copper and zinc, Antioxidants, 9: DOI: 10.3390/antiox9111117

Schwarz M, Lossow K, Schirl K, Hackler J, Kopp JF, Renko K, Schwerdtle T, Schomburg L, Kipp AP (2020). Copper interferes with selenoprotein synthesis and activity, Redox Biol., 37: DOI: 10.1016/j.redox.2020.101746

Finke H, Winkelbeiner N, Lossow K, Hertel B, Wandt VK, Schwarz M, Pohl G, Kopp JF, Ebert F, Kipp AP, Schwerdtle T (2020). Effects of a cumulative, suboptimal supply of multiple trace elements in mice: trace element status, genomic stability, inflammation and epigenetics, Mol. Nutr. Food Res., 1:e2000325. doi: 10.1002/mnfr.202000325

Lossow K, Kopp J, Schwarz M, Finke H, Winkelbeiner NL, Renko K, Meci X, Ott C, Alker W, Hackler J, Grune T, Schomburg L, Haase H, Schwerdtle T, Kipp AP (2020). Ageing affects sex- and organ-specific trace element profiles in mice, Aging US, 12: 13762-13790; https://pubmed.ncbi.nlm.nih.gov/32620712/

Hauffe R, Stein V, Chudoba C, Flore T, Rath M, Ritter K, Schell M, Wardelmann K, Deubel S, Kopp JF, Schwarz M, Kappert K, Blüher M, Schwerdtle T, Kipp AP, Kleinridders A (2020). GPx3 dysregulation impacts adipose tissue insulin receptor expression and sensitivity, JCI insight, 5 (11):e136283. doi: https://doi.org/10.1172/jci.insight.136283

Baudry J, Kopp JF, Boeing H, Kipp AP, Schwerdtle T, Schulze MB (2019). Changes of trace element status during aging: results of the EPIC-Potsdam cohort study, Eur. J. Nutr., doi: 10.1007/s00394-019-02143-w

Schwarz M, Lossow K, Kopp JF, Schwerdtle T, Kipp AP (2019). Crosstalk of Nrf2 with the trace elements selenium, iron, zinc, and copper, Nutrients, Sep 5;11(9); https://pubmed.ncbi.nlm.nih.gov/31491970/

Bornhorst J, Kipp AP, Haase H, Meyer S, Schwerdtle T (2017). Trace elements risks and benefits; the crux of biomarkers, Trends in Analytical Chemistry, available online 15 November 2017, https://doi.org/10.1016/j.trac.2017.11.007

Kipp AP, Deubel S, Arnér ESJ, Johansson K (2017). Time- and cell-resolved dynamics of Nrf2, HIF and NF-κB in spheroids enriched for cancer stem cells, Redox Biol. 10:403-409. https://doi.org/10.1016/j.redox.2017.03.013

Project Kipp (Second funding period): Interactions of trace elements in modulating the immune response during acute and chronic inflammation in mice

In TraceAge I, we could show that supplying mice with low amounts of the trace elements (TE) Cu, Fe, I, Mn, Se, and Zn (TE-) results in growth retardation and increased spleen weight in comparison to mice with adequate TE intake. In line with splenomegaly, serum levels of the inflammatory mediators TNF-α and CRP were increased. Based on our results, it appears that the immune system is very sensitive towards changes in TE intake. During aging, a low-grade systemic inflammation, called inflammaging, has been described. Thus, it is tempting to speculate that older organisms might have another need for TE to cope with inflammation than younger individuals. To address this, we aim to combine our established TE- regime with models of acute and chronic inflammation in young and old mice by applying the DSS model to induce colitis and LPS injection to study systemic inflammation. Besides TE profiles, inflammatory parameters as well as intestinal integrity will be analyzed. Vice versa, it is well-established that TE homeostasis is regulated in a different manner under conditions of inflammation as part of the so-called nutritional immunity. Thus, we aim to understand, how an acute and chronic inflammation affect the TE status and their biomarkers. Both questions will be addressed in mice and complemented with mechanistic studies conducted in cell culture. This project is supposed to provide the basis for considering all six TE in the future to better characterize and eventually improve the health status of humans suffering from acute and chronic inflammation.

 

2. Regulation and function of glutathione peroxidase 2 and other selenoproteins

In a model of inflammation-induced colorectal carcinogenesis, we showed that glutathione peroxidase 2 (GPx2) acts anti-inflammatory, which thus reduces tumor growth. In contrast, GPx2 supported tumor development in a model of sporadic colon cancer. The current project aims to elucidate molecular mechanisms underlying these contradictory effects. In addition, we aim to study further less characterized selenoproteins such as SELENOH.

Key publications:

Koeberle SC, Gollowitzer A, Laoukili J, Kranenburg O, Werz O, Koeberle A, Kipp AP (2020). Distinct and overlapping functions of glutathione peroxidases 1 and 2 in limiting NF-κB-driven inflammation through redox-active mechanisms, Redox Biol., 28:101388. doi: 10.1016/j.redox. 2019.101388.

Bertz M, Kühn K, Koeberle SC, Müller MF, Hoelzer D, Thies K, Deubel S, Thierbach R, Kipp AP (2018). Selenoprotein H controls cell cycle progression and proliferation of human colorectal cancer cells, Free Radic. Biol. Med., available online 9 January 2018, https://doi.org/10.1016/j.freeradbiomed.2018.01.010

Lennicke C, Rahn J, Wickenhauser C, Lichtenfels R, Müller AS, Wessjohann LA, Kipp AP, Seliger B (2017). Loss of epithelium-specific GPx2 results in aberrant cell fate decisions during intestinal differentiation, Oncotarget, 9:539-552. https://doi.org/10.18632/oncotarget.22640

Hiller F, Besselt K, Deubel S, Brigelius-Flohé R, Kipp AP (2015). GPx2 induction is mediated via STAT transcription factors during acute colitis, Inflamm. Bowel Dis. 21:2078-2089. https://doi.org/10.18632/oncotarget.22640

Emmink BL, Laoukili J, Kipp AP, Koster J, Govaert KM, Fatrai S, Verheem A, Steller EJA, Brigelius-Flohé R, Jimenez CR, Borel Rinkes IH, Kranenburg O (2014). GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer, Cancer Res. 74:6717-6730. https://doi.org/10.1158/0008-5472.CAN-14-1645

Müller MF, Pommer S, Florian S, Osterhoff M, Esworthy RS, Chu FF, Brigelius-Flohé R, Kipp AP (2013). Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development, PLoS ONE 8: e72055. https://doi.org/10.1371/journal.pone.0072055

Brigelius-Flohé R and Kipp A (2009). Glutathione peroxidases in different stages of carcinogenesis, Biochim. Biophys. Acta. 1790:1555-1568. https://doi.org/10.1016/j.bbagen.2009.03.006

 

3. Effects of a suboptimal selenium supply

We investigate the effects of a suboptimal selenium supply, which is prevalent in the German population. This is supposed to have negative effects on the immune system as well as on cancer development. The underlying molecular mechanisms need to be elucidated further.

Key publications:

Müller SM, Dawczynski C, Wiest J, Lorkowski S, Kipp AP, Schwerdtle T (2020). Functional biomarkers for the selenium status in a human nutritional intervention study, Nutrients, 12(3). pii: E676. doi: 10.3390/nu12030676

Speckmann B, Schulz S, Hiller F, Hesse D, Schumacher F, Kleuser B, Geisel J, Obeid R, Grune T, Kipp AP (2017). Selenium enhances hepatic DNA methylation and modulates one-carbon metabolism in the liver of mice, J. Nutr. Biochem. 48:112-119. https://doi.org/10.1016/j.jnutbio.2017.07.002

Lennicke C, Rahn J, Kipp AP, Dojčinović BP, Müller A, Wessjohann LA, Lichtenfels R, Seliger B (2017). Individual effects of different selenocompounds on the hepatic proteome and energy metabolism of mice, Biochim. Biophys. Acta. 1861:3323-3334. https://doi.org/10.1016/j.bbagen.2016.08.015

Kipp AP, Strohm D, Brigelius-Flohé R, Schomburg L, Bechthold A, Leschik-Bonnet E, Heseker H (2015). Revised reference values for selenium intake, J. Trace Elem. Med. Biol. 32:195-199. https://doi.org/10.1016/j.jtemb.2015.07.005

Hiller F, Oldorff L, Besselt K, Kipp AP (2015). Differential acute effects of selenomethionine and sodium selenite on the severity of colitis, Nutrients 7:2687-2706. https://doi.org/10.3390/nu7042687

Geillinger KE, Rathmann D, Köhrle J, Fiamoncini J, Daniel H, Kipp AP (2014). Hepatic metabolite profiles in mice with a suboptimal selenium status, J. Nutr. Biochem. 25:914-922. https://doi.org/10.1016/j.jnutbio.2014.04.003

Kipp AP, Banning A, van Schothorst EM, Méplan C, Coort SL, Evelo CT, Keijer J, Hesketh J, Brigelius-Flohé R (2012). Marginal selenium-deficiency down-regulates inflammation-related genes in splenic leukocytes of the mouse, J. Nutr. Biochem. 23:1170-1177. https://doi.org/10.1016/j.jnutbio.2011.06.011

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