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Priority Programme "Dynamics of Thiol-based Redox Switches in Cellular Physiology" (SPP 1710)
In recent years it has become evident that reactive oxygen and nitrogen species, despite their traditional reputation as causative agents of cell and tissue damage, act as physiologically essential messengers in signal transduction. The signaling properties of particular oxidants are primarily sensed and mediated by "Protein Thiol Switches", which are protein thiols that are specifically and reversibly modified by oxidation, thereby switching the protein between different conformational and functional states. In spite of the fundamental cell biological and medical importance of thiol switches we are only beginning to understand their principles of operation and specificity, their spatio-temporal dynamics, and their role in overall signal transduction. Based on this new perception and recent pioneering technical developments, particularly in redox imaging, redox proteomics and redox bioinformatics, we aim to synergistically address the following fundamental questions in the field of redox signaling and thiol-based redox regulation:
- What are the molecular mechanisms underlying protein thiol switches, and how can we explain the specificity and efficiency of reversible thiol switch oxidation and reduction?
- Which redox signaling events and thiol switch changes do occur in living organisms?
- Which redox switches are conserved and which are species-specific?
- What are the physiological roles of redox signals within the overall cellular signaling circuitry and decision making?
In order to adequately address these questions, novel interdisciplinary concepts and approaches shall be combined with stringent technological advancement:
- The precise biochemistry of the events under study shall be defined.
- High-resolution structural, functional, quantitative, and spatio-temporal information on in vivo redox events and their dynamics shall be obtained.
- Individual thiol switches shall be identified, monitored, and specifically manipulated in vivo.
- The physiological roles of thiol-switches shall be defined.
The Priority Programme aims to catalyse a decisive transition towards a true and thorough understanding of redox signaling cascades in the coming years. For this Priority Programme we propose an assembly of scientists uniquely positioned and selected for the task at hand, because of their conceptual and/or technical leadership. Within the programme, expertise and technology will be exchanged and made available in a highly synergistic way aiming to cross the borders between disciplines and to identify common principles of thiol switching across different model organisms - ranging from bacteria, protozoa, yeast and plants to mammals. A well-balanced analysis of model systems shall enable the SPP to define and to examine general redox signaling concepts of thiol switching, and at the same time, the rapid exchange and translation of results will speed up our understanding of thiol switching in the different model systems.
It is anticipated that within the SPP substantial progress will be made towards answering key questions on
- how oxidant signals actually propagate within cells,
- how thiol switches are mechanistically operated, and
- how redox signaling typically intersects with other forms of signaling, e.g. protein phosphorylation or acetylation.
The group will be able to compare redox signaling processes in different subcellular compartments and organisms and place them in a phylogenetic/evolutionary framework. It is expected that the in-depth unraveling of functional thiol switches, from the biophysical level to whole-organism physiology, will reveal general principles that may become paradigmatic for the whole field and have a high impact for biomedical and agronomical translation.
The projects of the SPP may be categorised into three classes:
- Projects characterising newly identified thiol switches, which are to be studied in mechanistic, functional, and structural detail.
- Projects identifying as yet unknown thiol switches, which are predicted to exist in a particular functional context and are planned to be characterised.
- Projects developing and applying engineered thiol switches to monitor (patho)physiological redox signaling in vivo.
It is expected that the proposals provide clear visionary aims.
The following research questions should be excluded:
- General studies on oxidative or nitrosative stress in (patho)physiological contexts.
- Studies based on broad notions of "oxidative stress" or "ROS" that do not explicitly define or address chemistry, specificity, mechanism or in vivo relevance.
- Studies on free radical biology and chemistry, which do not directly address thiol switches.
- Studies on redox-based intervention therapies, which do not directly address thiol switches.
- Studies on irreversible thiol modifications.
Proposals for the first three-year funding period can be submitted by 31 July 2013 (deadline) through the DFG's electronic proposal processing system "elan". In this system please select "SPP 1710" when submitting your proposal. All proposals must be written in English according to the DFG Proposal Preparation Instructions (DFG Form 54.01). Please include a title page with your name, your address, and the title of your project in your application.
You are further asked to send a PDF file of the application as well as an additional PDF file of the summary of the main application to the coordinator of the Priority Programme.
The review will be held during a proposal colloquium scheduled to take place in Bonn in late October 2013.
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