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Role of p63 and related pathways in epithelial stem cell proliferation and differentiation and in rare EEC-related syndromes.

Final Report Summary - EPISTEM (Role of p63 and related pathways in epithelial stem cell proliferation and differentiation and in rare EEC-related syndromes)

The focus and expected results of the EPISTEM project was to better understand the molecular basis of ectodermal dysplasia disease, to generate new knowledge on genes involved in epidermal development and disease and to translate this knowledge into applications that enhance human health. To this end both fundamental and applied research were involved. EPISTEM integrated multidisciplinary and coordinated efforts to understand the molecular basis of factors involved in epidermal stem cell generation, maintenance and differentiation and skin disease.

The epidermis is a multilayered, stratified epithelium that provides a physical barrier for the organism, protecting it from dehydration ultraviolet (UV) radiation and a variety of environmental insults. The epidermis is continuously renewed due to a regulated balance between proliferation and differentiation. This renewal capacity is due to the presence of epidermal stem cells. The concept that the transcription factor p63 is essential for formation of the epidermis arises from two lines of evidence. First, mice lacking p63 have no epidermis, and they also lack epithelial appendages, such as mammary, salivary and lachrymal glands, hair follicles and teeth. Second, mutations in the human p63 gene are responsible for ectodermal dysplastic syndromes.

But how does p63 contribute to the formation of the epidermis and maintenance of epithelial stemness? Do the p63 patient mutations have any diagnostic or prognostic value? What are the underlying mechanisms of its functions? What is the molecular pathogenesis of ectodermal dysplasia syndromes? Can we design a cure to reactivate mutant p63 molecules?

EPISTEM studied the p63-dependent signalling pathways to understand the role of p63 in ectodermal dysplasia syndromes, making use of different technologies (mutation analysis, micro-array, ChiP, transgenes, proteomics, in vitro skin cultures, crystallography, etc.). In addition, studies within our consortium indicated the involvement of the p63 transcription factor in the maintenance of epithelial stemness. Overall, EPISTEM formed a tight network with many interactions between the different work packages and partners involved. This enabled EPISTEM to accomplish substantial breakthroughs in our understanding of the role of p63 in health and disease.

Major achievements to date inlcude:
- Establishment of the largest collection in the world of biopsies, cells, and DNA derived from ~300 patients with mutations in the p63 gene.
- We are currently gaining profound knowledge on the genotype-phenotype correlation in ectodermal dysplasia patients. This can be of major social impact because it may become possible to predict disease progression or spontaneous disease improvement, depending on the type of mutation found in these patients.
- Epistem established cellular systems, both human and mouse, that mimic embryonal stem cell progression to ectodermal commitment and keratinocyte differentiation. Moreover, we (as well as other groups) found that p63 is crucial for maintaining the epidermal stemness. These insights could have significant importance for skin regeneration therapies such as in burn patients.
- Continuous and overlapping expression profiling enabled us to get a better view of which target genes of the p63 transcription factor are important for driving epidermal differentiation and maintaining the stemness character of the epidermal stem cells. EPISTEM developed BioIT approaches that enable comparison of the different data sets obtained within the consortium and available in literature.
- EPISTEM developed a number of mouse models by introducing human patient-related p63 mutations in the mouse, which could mimic human disease. This will enable us to better understand the effect of the different p63 mutations in patients and to test new therapeutic approached developed within the EPISTEM consortium.
- Finally, yet importantly, we identified small compounds that can rescue the transcriptional deficiency of some patient-related p63 mutants in vitro. We are currently screening the effects of these drugs in several cellular assays available within the consortium. The ultimate goal is to test these compounds on the mouse ectodermal dysplasia disease models that are being developed within the EPISTEM consortium.

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