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Implication of vitamin D and Wnt signaling crosstalk in epidermal keratinocyte stem cell fate. Role in skin morphogenesis and in epidermal tumorigenesis


The major goal of the proposed project is to study the role of vitamin D and Want signalling in skin morphogenesisand homeostasis, and in the alteration of these processes during the development of neoclassic and alopecia. For that purpose we will develop different experiments with keratinocytes and transgenic mice. First we will describe the interplay between vitamin D or some of its non-hypercalcemic analogues and Wntsignaling in different keratinocytes types, isolated from human and mice epidermis. One subpopulation of thesekeratinocytes is stem cells, which are able to regenerate all cell lineages present in the epidermis. We will express a modified vitamin D receptor (VOR), ÿ-catena or Left proteins (Want effectors) in these keratinocytes by retroviral infection. Then we will treat these cells with vitamin D or its analogues and analyse how their capacity to differentiate into the different keratinocyte lineages is modified. We will analyse how these genetically modified cells are able to regenerate an intermolecular epidermis (IFE), and which of them develop alterations during this process. We will study the changes in gene expression profiles promoted by those genetic modifications or by vitamin D treatment, using microarray analysis. In this way, we will be able to isolate new genes whose expression are regulated by every signalling pathway, and will define its implication in epidermal morph genesis invitro. The results obtained with these experiments will permit us to design the appropriate transgenic mice, expressing those proteins involved in vitamin D and Want signalling pathways, which are implicated in skin morphogenesis. We will use epidermal cell type specific keratin promoters to express those proteins into concrete keratinocytepopulations, including stem cells. Then we will study how modifying these proteins alter epidermalmorphogenesis, including the development of tumorigenesis, alpaca, and epidermal cysts.

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Lincoln's Inn Field 61
United Kingdom