Chemotherapy induced alopecia (CIA) in cancer patients results in emotional stress, but efficient treatment to prevent CIA is currently unavailable. Hair follicles physiologically undergo cycles of growth (anagen), regression (catagen), quiescence (telogen) and regeneration, and this cyclic behavior is regulated by a molecular clock intertwined within the interactions that couple epithelial stem cells and their mesenchymal niche. During chemotherapy, apoptosis within the proliferating matrix cells interferes with hair production, resulting in hair loss. The latter is accompanied by two dystrophic events; dystrophic anagen that temporarily halts the follicle in anagen and dystrophic catagen that prematurely induces the catagen phase. The current paradigm solely attributes both events to the apoptotic activity of p53 in the proliferating matrix cells of the epithelial compartment. We propose to explore a new paradigm in which p53 activation in the mesenchymal niche of the hair follicle during chemotherapy drives dystrophic catagen. We suggest the existence of an autoregulatory loop between Hdac1, Hdac2, p53 and Mdm2 in the mesenchymal part of the follicle, known as the dermal papilla (DP), that during chemotherapy resets the hair cycle clock to prematurely induce catagen and arrest the follicles in telogen. To test this hypothesis, we will use unique tools to genetically manipulate the components of this loop specifically in mouse DP. Furthermore, by combining in-situ hybridization, immunostaining, and pharmacological intervention, we will further dissect the molecular interactions and structure of this regulatory network during chemotherapy. Understanding the molecular interactions between the components of this autoregulatory network will provide insights into novel routes to prevent CIA.
Candidates should be highly motivated, seeking to broaden their understanding in stem cell biology. The PhD study involves working intensively with mice and includes a wide range of technologies. Experience in molecular biology is an advantage.
The position is funded for 4 years and can start immediately. Applications should include a CV, the academic achievements, a brief statement of research interests including past experience and names of at least 2 referees. Applications will be accepted until positions are filled. Contact : David Enshell-Seijffers (firstname.lastname@example.org).
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