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TRR 353:  Regulation of cell death decisions

Subject Area Biology
Medicine
Term since 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 471011418
 
The death of individual cells is a frequent event in a mammalian organism, and aberrations in cell death may have severe consequences to human health. In many, probably most instances, cell death is regulated, i.e. occurs as the result of cell-intrinsic signaling. The best-investigated form of regulated cell death, apoptosis, has been known for about 50 years. Additional, distinct cell death modalities have been discovered more recently, including necroptosis, pyroptosis, ferroptosis and oxeiptosis. A multitude of signaling steps in cell death processes have been described. However, with the multitude of different cell types investigated, with the intersection of cell death pathways with other signal transduction events and the separate but similar activities of cell death signaling components, it has been impossible to date to derive a comprehensive conceptual or mechanistic picture of cell death in the human body. We believe that a critical issue on the way to understanding cell death is to appreciate how a cell makes the decision to die. This decision has a number of levels, and two important aspects are the molecular decision to undergo a specific form of cell death, and the decision to make the choice of cell death modality. These two key points will form the focus of this program. In area A, we will endeavor to understand the decision to die. We define separate starting points where this decision may originate: the decision may be made at the level of stress integration by a cell, of signal integration by identified signaling hubs, or of terminal execution of cell death. Projects will investigate for instance signals through death receptors, signals generated by infection with exemplary pathogens, or signals generated by multi-functional transcription factors. Decisions by signaling hubs, such as the death-inducing signaling complex at membrane receptors and the mitochondrial BCL-2 family platform, will be interrogated, as will be cell death execution by membrane pores. The projects will tackle the question of the choice of cell death modality. Even identical stimuli may trigger different forms of cell death. How this decision is made is almost entirely unclear. The projects will investigate for example the cell type dependency of this decision, the role of subcellular origin of the signal and of post-translational modifications of key signaling molecules and hubs. The scientific spectrum reaches from basic biophysical questions to clinical application. The individual projects achieve coherence – in addition to the two main conceptual questions - through the focus on a limited number of cell death modalities and on common signaling molecules and hubs. Two service projects support all scientific projects. The work of this consortium will contribute to establishing fundamental principles of cell death decisions in basic biology and human pathology.
DFG Programme CRC/Transregios

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Applicant Institution Universität Konstanz
 
 

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