Research Projects
Overview
The overarching goal of the Walczak Laboratory is to provide a better understanding of the physiological interplay between cell death, ubiquitin and inflammation in the generation of immunity and how this functional interplay, on the one hand, controls disease but, on the other, when perturbed can instead become causative for pathologies such as cancer, autoimmune diseases or those that are induced as a consequence of an infection.
Death receptors and their ligands –between “holy grails“ and “dangerous liaisons“ in cancer, immunology, and immunopathology
In an adult human, billions of cells undergo suicide every day. Programmed cell death is a self-protective mechanism: it is triggered, for example, when cells are irreparably damaged. Normally, the body then produces new cells so that there is a balance between cell death and cell propagation. Disturbances in these mechanisms are thought to be crucial for the development of cancer and autoimmune diseases. This is where the research of the Walczak lab comes in. Amongst other things, they have demonstrated the role of various receptors, ligands and signalling molecules in controlling cell death and inflammation. Insights of this kind lay the foundation for new approaches to therapy. By activating a suicide programme known as apoptosis specifically in cancer cells, these cells can be exterminated, importantly without damaging the surrounding tissue. The precise molecular mechanisms how this can be achieved are the subject of ongoing research in the Walczak lab. Cell death can, however, also drive inflammation and, thereby, be causative for severe pathologies. The Walczak lab has discovered that this previously unrecognised aetiology of inflammation can be causative for chronic inflammatory and autoimmune disorders. It is entirely possible that this newly discovered disease aetiology may also extend to severe pathologies that are triggered by infectious agents which cause untoward cell death and consequent inflammatory disease. As a Humboldt Professor at the University of Cologne, Henning Walczak will pursue the “from bench to bedside” approach combining preclinical with clinical research with the ultimate goal of achieving effective treatments for the afore-mentioned severe diseases.
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The role of cell death in inflammation and inflammation-related disorders
Inflammation is a hallmark of many diseases. Until recently, cell death was not considered to cause inflammation-associated diseases. The tumour necrosis factor (TNF) is a protein made in our body in response to stress. A few years ago, the Walczak lab demonstrated that in mice in which a crucial component is missing from the TNF signalling pathway, TNF induces aberrant cell death and that this cell death is cause, not consequence, of inflammatory disease in these mice. The group now discovered that this new paradigm extends to other factors similar to, but distinct from, TNF. It may therefore be necessary to prevent the different cell-death-inducing factors simultaneously from inducing cell death to achieve therapeutic benefit. This is the new treatment paradigm the Walczak lab will address through adequate in-vitro and in-vivo systems. If successful, the results of the Walczak group may provide benefit to patients suffering from inflammation-associated diseases, possibly including those who do not benefit from TNF inhibition – or indeed from the sole inhibition of TNF.
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Understanding and harnessing death receptor–ligand systems in small cell lung cancer (SCLC)
This research project is aimed understanding and therapeutically harnessing the tumour-supportive and immuno-suppressive functions of different death receptor–ligand systems in SCLC. It aims to understand the tumour and immuno-biology underlying death ligand-mediated promotion of SCLC growth, metastasis and immune evasion.
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LUBAC and its components in TNF-induced cell death, inflammation, immunity and disease
Receptor-ligand-mediated signalling in cell death, inflammation and immunity is regulated by a fine-tuned system of post-translational modifications by phosphorylation, ubiquitination and their respective reversals. The linear ubiquitin chain assembly complex (LUBAC) modulates signalling via the TNF–TNFR1 system. The Walczak group previously discovered that LUBAC and the linear ubiquitin chains it creates are crucial for the different TNFR1 signalling outputs by enabling full gene activation and preventing cell death. These studies established cell death as a trigger of inflammation and inflammatory disease. The aim of this project, which the Walczak group performs in collaboration with the group of Dr Nieves Peltzer (Centre for Molecular Medicine Cologne; CMMC), is to understand and further dissect the biochemistry and function of LUBAC and its individual components in health and disease.
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