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Modulation of signaling and epidermal differentiation by desmosomal adhesion
Third-party funded project
Project title Modulation of signaling and epidermal differentiation by desmosomal adhesion
Principal Investigator(s) Spindler, Volker
Project Members Siketanc, Matej
Beyersdorfer, Vivien
Organisation / Research unit Departement Biomedizin / Cell Adhesion (Spindler)
Project start 01.01.2021
Probable end 31.12.2024
Status Active
Abstract

Adhesion between cells is essential to develop and maintain integrity and homeostasis of multicellular organisms. Transmembrane adhesion molecules are often clustered to form cell-cell junctions, such as adherens junctions and desmosomes. Adherens junctions are well established structures important both for intercellular adhesion and for coupling extracellular cues with cellular responses. With regard to desmosomes, the view is currently shifting from being “sticky glue” to junctions actively involved in shaping cell behavior through modulation of intracellular signaling pathways. The mechanisms, however, are only partially understood, although dysfunctional desmosomal adhesion cause severe diseases of the skin and the heart. The aim of this grant is to better understand the functions of desmosomes both in physiological and diseased states using the epidermis as model system. We will elucidate whether and how desmosomes sense contact to other cells and translate this information into signaling and, in turn, lead to modification of cellular responses. In the first part, we will apply a combination of activity sensors for specific signaling molecules and single cell force spectroscopy to outline the impact of cell contact, adhesion molecule clustering and tension through desmosomal junctions for signaling. The second part will elucidate roles of desmosomal molecules for differentiation in reconstituted human epidermis and, using single molecule force spectroscopy, will test the hypothesis that the binding properties of desmosomal cadherins change during epidermal differentiation. In the third part, we will determine the relevance of these mechanisms for adaption to mechanical stress and in the context of autoimmune and genetic desmosome diseases. In the last part, we will evaluate how desmosomal function and plasticity is regulated by specific signaling pathways and finally test novel regulators of desmomomal adhesion. The work planned within this grant aims at identifying novel functions of desmosomal adhesion and will establish new paradigms how cells autonomously adapt to constantly changing mechanical stresses. The results should be applicable to many other desmosome-bearing tissues and raise the understanding of complex and devastating diseases of the skin and the heart.

Financed by Swiss National Science Foundation (SNSF)
   

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29/03/2024