SFB 815:  Redox-Regulation: Generating Systems and Functional Consequences

• Subject Area: Medicine ; Biology
• Term: from 2009 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 61867463

Redox-regulated processes are positioned at the interface between genome coded structure/function relationships and their adaptation to the availability of oxygen, the generation of superoxide, nitric oxide, and hydrogen sulfide as well as their metabolites. In analogy to the add-on of the epigenome to the genome we have to expand the proteome by the epiproteome, or more specifically the redox-proteome. The posttranslational reversible protein modification via redox signals constitutes a communication system to control cellular functions. Redox-regulated processes affect (i) changes in enzyme activity or the DNA-binding capacity of transcription factors, (ii) aggregation of proteins, (iii) protein stability and/or function, and (iv) compartmentalization, cell-matrix and cell-cell communications, respectively. With these considerations the Collaborative Research Centre (CRC) studies integrative processes such as cell differentiation, cell polarization, inflammation, pain, diabetes, electric conduction, and infection. During the first funding period we focused on “Activation of Generating Systems”, i.e. NADPH-oxidases, respiratory chain complexes, prolyl hydroxylases, and cystatione γ-lyases. In the second funding period key aspects comprised “Investigations towards distinct effector structures” and functional consequences affecting inflammation, mitochondrial respiration, and the control of individual signaling complexes. The aim of the third funding period is to consolidate our knowledge of generating system and the epiproteome to further advance our understanding of the “Redox imprinting of biological systems”. As redox imprinting of biological systems we define (i) methods to visualize redox-imprints, like the identification of (bio-)markers in relation to distinct generating systems, (ii) identification and mechanistic characterization of redox junctions in complex biological signaling cascades, (iii) the link between the epiproteome and metabolome, and (iv) questions approaching therapeutic options and generalizing our observations. In particular, the dynamic responses of molecular, cellular, and in vivo systems following the activation of generating systems, the temporal sequence of biological changes, and the reversibility will show how these systems are balanced, how they can be adjusted, and which functional redox-based consequences will result for cells, organs, and/or organisms. This might be linked to the onset of diseases but also healing processes. An integral part for the CRC is the analysis of posttranslational redox modifications within the proteome, using mass spectrometry. At an interdisciplinary level the CRC aims at contributing and understanding the imprinting of cardiovascular, oncological/immunological, and neurological systems by identifying and modulating redox-signatures. A detailed knowledge and an appreciation on general concepts towards redox-networks should enable others to use our findings and apply them to future question in biomedicine.

• DFG Programme: Collaborative Research Centres

Completed projects

• A01 - Nox4 as a redox switch in epigenetics and metabolism (Project Heads Brandes, Ralf P. ;  Schröder, Ph.D., Katrin )
• A02 - Mechanisms to control the mitochondrial ROS production within the cellular redox signaling (Project Head Dröse, Stefan )
• A03 - Redox regulation of the Nox2 and B7-H1 mRNA stability (Project Head von Knethen, Andreas )
• A04 - ROS signaling in normal hematopoiesis (Project Head Grez, Manuel )
• A05 - Crosstalk between matrix and ROS signaling during renal inflammation and fibrosis (Project Head Schaefer, Liliana )
• A06 - Redox-regulation of integrin-matrix contacts during cell adhesion and migration (Project Head Eble, Johannes Andreas )
• A07 - Hydrogen sulfide (H2S) as a regulator of redox homeostasis during glomerulonephritis (Project Head Pfeilschifter, Josef M. )
• A08 - Consequences of chronic hypoxia and HIF-1/HIF-2 in regulating function and plastic-ity of macrophages and tumor cells (Project Head Brüne, Bernhard )
• A09 - Metabolic Syndrome: reactive oxygen species-mediated proinflammatory signaling via the ER in macrophages during impaired wound healing (Project Head Frank, Stefan )
• A10 - Dissecting the ROS-regulatory mechanisms of Sestrin 2-dependent mTORC1 suppression (Project Heads Kurrle, Nina ;  von Melchner, Ph.D., Harald ;  Serve, Hubert )
• A12 - Nucleoredoxin as regulator of neuronal activity and plasticity (Project Head Tegeder, Irmgard )
• A13 - Mechanisms and consequences of a defect redox control of Kv4.3 channels in Morbus Parkinson (Project Head Roeper, Jochen )
• A14 - Nox4-dependent mechanisms in neuropathic pain and pruritus signaling cascades (Project Heads Geißlinger, Gerd ;  Kallenborn-Gerhardt, Wiebke )
• A16 - Functional consequences of a redox regulated activation of calpain in diabetes (Project Head Fleming, Ph.D., Ingrid )
• A17 - Mechanism and functional consequences of the Toll-like receptor 2-mediated alteration of the mitochondrial ROS production (Project Heads Mersmann, Jan ;  Zacharowski, Ph.D., Kai )
• A19 - Influence of hypoxia-activated transcription factors on bacterial infections (Project Head Kempf, Volkhard A. J. )
• A20 - Function and regulation of the SUMO system during hypoxia (Project Head Müller, Stefan )
• A21 - Molecular mechanisms of the redox regulation of necroptosis during acute lymphatic leukemia (Project Head Fulda, Simone )
• A22 - Role of the phospholipid hydroxyperoxide glutathion peroxidase (PHGPx) GPx4 in murine hepatozytes and hepatocarcinogenesis (Project Head Greten, Florian R. )
• MGK - Integrated Research Training Group (Project Heads Brandes, Ralf P. ;  Tegeder, Irmgard )
• V - Administration (Project Heads Brandes, Ralf P. ;  Brüne, Bernhard )
• Z01 - Redox-Proteomics (Project Head Wittig, Ilka )

• Applicant Institution: Goethe-Universität Frankfurt am Main
• Spokesperson: Professor Dr. Bernhard Brüne