CRC/Transregio TRR 353

Regulation of cell death decisions

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.

In this consortium, we want to advance our knowledge on how the sensitivity of an individual cell to a cell death-inducing stimulus is regulated, how to qualitatively or quantitatively predict this response from measurable parameters, and how to steer a cell in its death-survival decision and the chosen cell death modality. The work of this consortium will contribute to establishing fundamental principles of cell death decisions in basic biology and human pathology.