Molecular mechanisms of apoptosis and necrosis
Cell death is a crucial process in development, homeostasis and (patho)physiology. In normal conditions about 100 billion cell die mostly by apoptosis. However, many diseased conditions are associated with a deregulated balance in cell death. Too much or too sensitive cell death is associated with inflammatory and degenerative diseases, while too little or too insensitive cell death is associated with development of cancer and with therapeutic resistance. This implies that depending on the particular role of cell death in a given disease therapeutic strategies could be envisioned that either sensitize or desensitize cell death pathway. However, in order to do so, a profound knowledge is required not only of cell death pathway but also on the molecular mechanism that regulate these cell death pathways.
The research unit of Peter Vandenabeele focuses on the molecular mechanisms of different cell death modalities (a.o. apoptosis, necroptosis, ferroptosis, immunogenic cell death) and cellular stress (ER stress), their regulation, their functional interactions and the role herein of caspases, RIPK and other signalling molecules. The unit is both interested in cell autonomous as well as intercellular aspects of cell death and cellular stress such as communication with the innate immune system. These processes are studied in an integrated way at the level of biochemistry, cell biology, development of conditional transgenic models and their role in various diseases models such as sepsis, skin inflammation and cancer, and intestinal inflammation and cancer. In order to identify novel targets in signalling of cell death modalities we developed a cellular screening platform in which we screen customized functional classes of libraries of sh/siRNAs (kinases, ubiquitylating enzymes, etc.), libraries of known clinical drugs and series of chemical compounds. The hits are then further examined in cellular systems and in experimental disease models for their potential to modulate cell death pathways or to influence disease models.
In the Bertrand team, we focus on the elucidation of the molecular mechanisms regulating stress-induced cell survival/death, as well as innate immune/inflammatory responses, with a particular interest on the role of post-translational modifications, such as phosphorylation and ubiquitylation. This group is currently characterizing the cell death checkpoints (apoptotic and necroptotic) downstream of TNFR1, as well as identifying new regulators of death induced by endoplasmic reticulum (ER) stress.
In the Declercq team we mainly focus on understanding the role of RIPK1, 3 and 4 and MLKL in inflammation and cancer in the skin. Therefore we make use of cellular models and in vivo mouse models. We are especially interested in investigating whether RIPK1, RIPK3 or MLKL can serve as therapeutic targets in skin inflammation. In addition, we investigate the functions of RIPK4 and secondary modifications controlling its activity.
The Jonathan Maelfait team studies how host cells discriminate between nucleic acids accumulating in virally infected cells and endogenous nucleic acids present in healthy cells. Nucleic acid sensors are key mediators of the innate antiviral immunity. Their activation occurs through the recognition of virus- or cell-derived nucleic acids. Although the recognition of viral RNA or DNA is critical to mount an antiviral immune response, sensing of self-nucleic acids has important implications in the etiology of autoinflammatory diseases.
The Tom Vanden Berghe team (90% UAntwerpen, 10% UGent-IRC) performs applied research in the context of cell death/ferroptosis, inflammation and disease. In particular, the Vanden Berghe team studies the mechanisms, diagnostics and intervention strategies in the field of critical illness (precision medicine, sepsis and multi organ failure), brain injuries (multiple sclerosis, ischemic and hemorrhagic brain stroke), chronic kidney disease, vascular calcification and bone metabolism.
Our fundamental research may lead to therapeutic applications in cancer, inflammatory and neurodegenerative diseases, and skin pathologies.
Areas of Expertise
- Signal transduction in cell death and inflammation
- Mitochondrial functions in cell death
- Role of caspases and RIP kinases, and their substrates in cell death and inflammation
- Transgenic mice for cell death and inflammation
- Cell death and inflammation in the skin and intestine
Technology Transfer Potential
- Molecular targets in cell death and inflammation
- Molecular targets in skin and intestinal diseases
Bibliography
- Full bibliography Visit ➚