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SFB 1430:  Molecular Mechanisms of Cell State Transitions

Subject Area Biology
Chemistry
Medicine
Term since 2021
Website Homepage
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 424228829
 
Cell proliferation needs to be tightly controlled to ensure organismal development and tissue regeneration, while preventing neoplastic disorders. One hallmark of this control is the establishment of distinct, biochemically or epigenetically defined cell states and the regulated transitions between these states. Cell state transitions regulate the ordered progression through the individual stages of the cell division cycle, but also govern the conversions between fast and slow cycling cell states that underlie cancer and cancer cell plasticity. The major regulators that establish and maintain cell states have been studied in detail. The ordered transitions, however, rely on switch-like signalling changes that are controlled by diverse and poorly understood trigger mechanisms. A prime example of such a trigger mechanism is the machinery that senses successful chromosome attachment to the mitotic spindle and then activates a signalling cascade to proceed with cell division. Similar principles underlie DNA damage and other stress sensors that elicit cell cycle checkpoint activation, the molecular links between cytoskeleton or metabolic alterations to cell states, as well as changes in epigenetic regulators that govern cancer cell state transitions. A comprehensive understanding of these processes can only be achieved by deciphering the underlying trigger mechanisms in molecular detail. However, progress has been hampered by the inherent experimental challenges imposed by the velocity of the critical events, cell-to-cell heterogeneity, and pathway redundancies. This initiative now aims to overcome these limitations in an interdisciplinary effort that integrates biologists, molecular oncologists, and chemists. These fields will be bridged in a unique manner by jointly developed and applied direct methodologies such as advanced biochemical reconstitution and novel approaches of acute chemical or optical perturbation combined with real-time monitoring to unravel the key factors and regulatory mechanisms responsible for triggering cell state transitions. Specifically, we want to decipher how the key triggers sense, integrate and transmit signals to regulatory circuits that define cell states. Projects are chosen to range from cell cycle progression to state transitions that underlie cancer cell plasticity and cancer therapy resistance. The joint effort will stimulate the development and use of new approaches and research avenues in the individual projects to uncover underlying mechanisms, allow identification of common principles and reveal novel means of regulation. Thus, our concerted approach will bring together in a unique manner the methodological and biological expertise that is suited to tackle the current challenges in unravelling cell state transitions. This strategy will lead to a major conceptual advance in our understanding of the regulation of cell proliferation and is likely to reveal unanticipated strategies for therapeutic intervention
DFG Programme Collaborative Research Centres

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Applicant Institution Universität Duisburg-Essen
 
 

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