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Research focus and intent

Our research is organized in three consecutive steps: (1) We aim to understand the detailed molecular mechanisms by which redox signals are transmitted inside cells. (2) We make use of mechanistic insights to create tools that enable monitoring and manipulating redox signals inside living cells and model organisms. (3) We employ these tools to obtain more detailed understanding of redox homeostasis in either healthy or malignant situations. We are interested in intervention strategies that enhance cytoprotective signals in healthy cells and disrupt them in malignant cells.

1. Molecular mechanisms of redox signalling and protein redox regulation

Endogenously produced H2O2 acts as a signaling molecule. To transmit a signal, it facilitates the oxidation of particular cysteine residues on particular proteins in particular subcellular locations. However, it is not easily explained how a small diffusible molecule can oxidize proteins in a highly selective manner. To add to the mystery, cells are brimming with highly reactive H2O2 scavengers, called thiol peroxidases, which should quickly mop up newly formed H2O2 before it can react with other proteins. Thus, the question of how redox-regulated proteins can be efficiently oxidized by nanomolar signaling concentrations of H2O2 in the presence of highly efficient H2O2 scavengers adds to the long-standing conundrum of redox signaling.

Growing evidence now suggests that thiol peroxidases do not just eliminate H2O2. It turns out that they can pass on oxidizing equivalents from H2O2 to other proteins through protein-protein interactions. Intriguingly, such redox relays can explain the specificity, sensitivity and efficiency of H2O2 mediated redox signaling. We recently described the first example of a thiol peroxidase-based redox relay in mammalian cells (Sobotta et al., 2015).

We now address the following questions: (i) How common are peroxidase-based redox relays in mammalian cells? What is their overall importance as mediators of protein thiol oxidation? (ii) How exactly are oxidizing equivalents transmitted from thiol peroxidases to target proteins? (iii) How do peroxidases and target proteins recognize each other prior to the transmission of oxidation? (iv) Which other enzymes may employ relay mechanisms to transmit oxidation to specific target proteins?

2. Visualization and manipulation of redox processes in vivo

Design and advancement of genetically encoded redox probes
We are exploring new design strategies for genetically encoded redox biosensors. The basic idea is to mimic the mechanisms of redox sensing and signaling that exist in nature. To this end we are engineering redox relays in which redox-sensitive fluorescent proteins exchange electrons with oxidoreductases, peroxidases or other enzymes. Our most recent development are H2O2 probes based on typical 2-Cys peroxiredoxins, which are amongst the proteins with the highest known sensitivity towards H2O2 (Morgan et al., 2016).

Pinpointing redox changes in the context of the whole organism
We are expressing genetically encoded redox probes in model organisms, from single-celled microbes to mammals, to visualize redox processes as they occur in living cells and in vivo. In the context of mouse models we aim to pinpoint and characterize redox changes caused by diet, physical activity, disease and pharmacological intervention. Our most recent development is a procedure that allows visualizing the in vivo redox state of genetically encoded redox biosensors within histological sections of murine tissues (Fujikawa et al., 2016).

Precision tools for in vivo redox intervention
Beyond detection and visualization, we also need strategies and tools to target and manipulate endogenous redox processes with chemical and spatial precision. To this end, we are combining redox imaging with genetic and genomic tools to systematically investigate the influence of gene products on redox homeostasis. We also screen for small molecules that either induce or inhibit defined redox processes in defined locations within living cells. In addition, we aim to better understand how some well-known drugs influence redox processes on the cellar and organismal level.

3. Understanding adaptive stress responses in normal and tumor cells

Metabolic adaptations to oxidative stress
When cells encounter oxidative stress, metabolic pathways re-organize rapidly to provide protective adaptation. One example is the re-routing of reducing equivalents into the NADPH-producing pentose phosphate shunt, which is triggered by oxidative inactivation of the glycolytic enzyme GAPDH (Dick and Ralser, 2015). We recently discovered mutants of GAPDH which lack oxidation sensitivity and thus fail to trigger metabolic adaptation under stress conditions (Peralta et al., 2015). Using genomic editing tools we now aim to understand the role of GAPDH oxidation sensitivity in tumor metabolism and growth.

Hormetic adaptations to mitochondrial dysfunction
Mild mitochondrial dysfunction, as for example provoked by calorie restriction or physical activity, is suspected to trigger adaptive alterations in gene expression that contribute to the maintenance of health. One key question is whether the emission of H2O2 by mitochondria plays a causal role in the initiation of such beneficial adaptations.

Disruption of adaptive redox homeostasis in tumor cells
It has been suggested that cancer cells produce endogenous oxidants more vigorously than most normal cells. This implies that many cancers may depend more heavily on highly upregulated reducing systems to keep overall redox homeostasis in balance. We are interested in small molecules that inhibit the maximal activation of reducing systems, thus potentially pushing tumor cells over their tolerable threshold of endogenous oxidant production.

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