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EPISTEM<br />
Role of p63 and Related Pathways in<br />
Epithelial Stem Cell Proliferation and<br />
Diff erentiation and in Rare EEC-Related<br />
Syndromes<br />
Summary<br />
The focus of EPISTEM is to generate new knowledge and<br />
translate it into applications that enhance human health. To<br />
this end both fundamental and applied research will be<br />
involved. EPISTEM integrates multidisciplinary and coordinated<br />
eff orts to understand the molecular basis of factors<br />
involved in epidermal stem cell generation, maintenance and<br />
diff erentiation and skin disease. Moreover, the core molecule<br />
that will be studied in this Integrated Project is p63 (and<br />
related pathways), a molecule genetically proven to be<br />
involved in the development of rare skin diseases. Collectively,<br />
the prevalence of ectodermal dysplasia syndromes (EDS) is<br />
estimated at seven cases in 10 000 births. Currently there is<br />
no cure for these patients. By creating the EPISTEM consortium,<br />
we want to address, from diff erent angles (i.e. via<br />
genetics, gene profi ling, molecular and cellular biology,<br />
structural biology, drug design and bioinformatics), the<br />
molecular pathways involved in epidermal dysplasia syndromes<br />
making use of diff erent technologies (mutation<br />
analysis, micro-array, ChiP, transgenes, proteomics, in vitro<br />
skin cultures, crystallography, etc.). Our consortium brings<br />
together leading European clinicians, geneticists, molecular<br />
and cellular biologists, structural biologists, a drug designer<br />
and bioinformatics specialists in the fi eld of p63 (and related<br />
molecules) research.<br />
Problem<br />
The core molecule that will be studied by the EPISTEM consortium<br />
is p63 (and related pathways), a molecule genetically<br />
proven to be involved in the development of rare skin<br />
diseases such as EEC syndrome (Ectrodactyly-ectodermal<br />
dysplasia – clefting), Hay-Wells (AEC) syndrome, Limb-mammary<br />
syndrome, ADULT syndrome, Rapp-Hodgkin syndrome<br />
and non-syndromic split hand-split foot malformation.<br />
Currently there is no cure for these patients.<br />
32<br />
Keywords | Epithelial stem cell | keratinocyte diff erentiation | p63 and family members | EEC-related syndromes |<br />
Aim<br />
• Collecting and culturing of keratinocytes from EDS<br />
patients with p63 mutations and extensive analysis of<br />
phenotype-genotype correlation. These keratinocytes<br />
will be used to uncover the role of p63 proteins and pathways<br />
in normal and abnormal skin development.<br />
• Building relevant in vitro and in vivo skin disease models<br />
for studying the role of p63 in EDS disease and the<br />
genetic assessment of novel pathways discovered during<br />
this project. These models will also be used for drug<br />
assessment.<br />
• Provide insight into the regulation and involvement of<br />
p63 and related pathways in skin diff erentiation, the maintenance<br />
of the proliferative capacity of epithelial stem<br />
cells and the transition of ectodermal cells to epidermal<br />
stem cells.<br />
• Screening for, and design of, novel therapeutic drugs,<br />
based on three-dimensional p63 models, that will refold/<br />
reactivate or inhibit p63 mutants and induce biological<br />
responses in relevant disease models.<br />
Expected results<br />
First of all, the EPISTEM consortium will generate a thorough<br />
insight into the molecular biology of a rare disease<br />
such as EDS, for which no cure is currently available. Secondly,<br />
characterising and understanding how epidermal<br />
stem cell maintenance is regulated by p63 could be benefi -<br />
cial for the treatment of burn victims since these stem cells<br />
could be used for tissue regeneration. So, in the long run, the<br />
EPISTEM research proposal may have a far broader impact<br />
on clinical practice and the biomedical industry than is currently<br />
estimated. Thirdly, this integrated project will generate<br />
knowledge and technology that is not only applicable to<br />
p63 itself, but also to its family members p53 and p73; p53<br />
is an important target that is mutated in most cancers and<br />
p73 is an important molecule for neurogenesis. Finally, from<br />
a technological point of view, the EPISTEM proposal will<br />
invest in the development of chIP (chromatin immunoprecipitation)<br />
on chip technology.<br />
Potential applications<br />
Drug-development for the cure of skin diseases, cancer, etc.<br />
and a wound-healing treatment.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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