microRNAs ; ultraviolet light; skin; keratinocyte; cancer; Notch; Nrf2; PPAR; in vivo delivery; transgenic mice
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The skin is an organ of great clinical relevance. It also provides an excellent model system to understand integrated control of tissue homeostasis under normal conditions, in response to external insults (most notably UV light), in the wound healing process, during aging, and in tumorigenesis. It is becoming increasingly clear that complex biological systems such as the skin are intrinsically “robust”, i.e. organized as scale-free networks, with most connections being made to critical “hubs” (or signaling centers). Several “hubs” that integrate and orchestrate the response of the skin to UV irradiation have been identified, and they include transcriptional regulators like p53 and its target Notch1, Nrf2 and PPARß/d. In concert with protein-encoding genes, microRNAs (miRNAs) play a key role in integrating multiple signaling inputs and coordinating the overall gene expression response of cells and tissues to changing environmental conditions. The main goal of this proposal is to explore the role that miRNAs play as integrating determinants of the UVB response of keratinocytes. More specifically, we will test the hypothesis that miRNAs control the acute UVB response of keratinocytes, impinging on intrinsic regulation of these cells and their modulation of other cell types, in a possible cross-talk with the p53/Notch, Nrf2 and PPARß/d pathways. We will further test the hypothesis that miRNAs play an essential function in the long-term UVB response of keratinocytes, in particular in skin cancer development.Using microarray analysis we have identified UVB-regulated miRNAs in acutely and chronically UVB-irradiated mouse skin as well as in human primary keratinocytes. Their roles in UV-mediated cell cycle arrest, differentiation, apoptosis, ROS production, and inflammation will be analyzed, as well as their capability to influence keratinocyte tumor formation. This will be achieved by transfection of keratinocytes with miRNA precursors (oligomiRs) and miRNA blocking oligonucleotides (antagomiRs) in conventional and organotypic culture conditions, human skin explants, and in vivo in mice. For the latter, novel strategies for in vivo delivery of miRNAs/antagomiRs to the skin will be developed. Putative targets of relevant miRNAs will be identified by combined bioinformatic and biochemical approaches, followed by in vitro and in vivo validation. Finally, cross-regulation between specific miRNAs and the p53/Notch1, PPARß/d, and Nrf2 pathways will be determined.These ambitious goals shall be achieved by a close collaboration between three groups with strong and complementary expertise in skin biology, and a fourth group with strong expertise in miRNA biology/technology. Additional expertise in bioinformatics is available through collaboration with an outside expert. The project is expected to shed light onto the mechanisms involved in the UV response of the skin and to identify key regulators involved in skin protection/repair after UV-induced damage. By bringing our laboratories together, we can use a combined comparative approach of the mouse and human systems, which is likely to produce significant novel insight with strong implications for human health. In addition, this project will strengthen the fields of skin biology/ miRNA biology in Switzerland, since it will promote the collaboration between groups with complementary expertise. Through this interaction, a new generation of young investigators will be trained in these areas of research.