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Research Summary

Desmosomes are adhesive cell-cell junctions that provide mechanical resilience and spatially coordinate signalling to control complex epithelial. The skin and the digestive tract are critical barriers between the human body and the environment. There is increasing evidence that desmosome dysfunction leads to loss of epithelial barrier function and is central for the onset and/or perpetuation of inflammatory disorders of human epithelial organs.
The focus of the TRR 425 “Desmosomal dysfunction in epithelial barriers” (DEFINE) will be on three human model diseases of desmosomal dysfunction, i.e. pemphigus vulgaris (PV), inflammatory bowel diseases (IBD) and eosinophilic oesophagitis (EOE). PV is caused by autoantibodies against components of desmosomes and presents with severe blistering of skin and mucosal surfaces, major risk of infections and increased body catabolism. IBD and EOE are also characterised by loss of barrier function of the intestinal mucosa and are linked to desmosomal dysfunction in a subset of patients.

In this consortium, basic researchers in cell biology and immunology with a focus on desmosomes in epithelial homoeostasis will join forces with clinician scientists dealing with human disorders of skin and digestive tract. This blend of researchers will be able to perform desmosome-related research on a much more complex level based on their shared views and insights. Focusing on proper and impaired desmosomal function of the major epithelial organs will be a novel, most instructive way to understand the complexity of desmosomal functions. We will first study the consequences of desmosomal impairment for disease pathogenesis. This will lead to a thorough understanding of desmosome function in epithelial homoeostasis by the regulation of barrier integrity, cellular signalling, tissue regeneration, and wound healing. Several members of this consortium have a common history in desmosome research based on their participation in FOR 2497 “Pemphigus – from Pathogenesis to Therapeutics” and the SPP 1782 “Epithelial intercellular junctions as dynamic hubs to integrate forces, signals and cell behaviour”. Initially, we will aim at identifying cell type-specific and common pathophysiologic traits in desmosomal dysfunction which induce distinct inflammatory signatures and clinical pathologies in skin and digestive tract. DEFINE will provide mechanistic links between desmosome defects and disease pathogenesis in the digestive tract. These findings will be exploited for targeted therapeutic strategies aimed at restoring desmosomal function. To foster research in this evolving field, we will make major efforts to train a new generation of early career scientists and clinical scientists at the cross-roads between basic and translational science. The TRR 425 DEFINE will close the gap between our limited understanding of fundamental functions of desmosomes in health and the impact of desmosomal dysfunction on human diseases.