PROJECT SUMMARY Skin repair after injury is a complex process that requires coordinate interactions between resident skin cells, recruited immune cells and result in local tissue deposition/remodeling. Cell-cell interactions during wound repair are regulated at several levels including signaling/transcription factor-mediated and epigenetic mechanisms, while it remains unclear how these mechanisms are altered during pathological skin repair. Hypertrophic scars commonly occur after burn, trauma or surgery, and are characterized by the excessive deposition of extracellular matrix with the inadequate remodeling, which result in severe physiological and psychological problems in patients. However, the effective prevention and treatment of the scars occurring as a result of tissue injury are still limited, at least in part, due to the challenges in translation of the data obtained in different animal (mouse, rabbit, pig) models to human skin and human skin scarring. One of the fundamental questions in modern biomedical research is the search for new model organisms that adequately reflect the mechanisms regulating human development, homeostasis and aging, as well as their alterations in human diseases. Naked mole rats (NMRs, Heterocephalus glaber) are unique long-lived mammals that possess marked resistance to cancer and other age-related pathologies and maintain sustained healthy life- span span for up to 32 years, which is approximately ten-fold longer compared to mice or rats. Comparative genome and transcriptome analyses revealed that the NMR genome show higher similarity to the human genome compared to mice and rats. Our preliminary data demonstrate that NMRs also possess the unique ability to regenerate skin wounds without scarring, thus suggesting them as the unique mammalian model for studying mechanisms preventing scar formation after injury in adult skin. In this exploratory grant, we will test a hypothesis that NMR skin serve as a unique model for studying mechanisms of wound repair and scar formation. This hypothesis will be addressed via two Specific Aims (R61 phase) and relevance of the data obtained on NMRs will be further validated on human skin (R33 phase). R61 phase: Aim 1. Characterize the NMR skin as innovative model for studying mechanisms of skin regeneration and wound healing. R61 phase: Aim 2. Define mechanisms contributing to scar-free wound healing in the NMR skin. R33 phase: Aim 3. Validate the relevance of distinct regulatory mechanisms controlling the scar- free wound repair process in the NMR skin to human skin. The generated outputs from this application will provide novel insights into fundamental mechanisms underlying scar formation after injury, enhance the innovative potential of securely establishing a place for the NMR as a model organism for studying the biology of human skin, as well as will promote the development of novel paradigms for modulation of wound healing and scar formation in humans.

PROJECT NARRATIVE Naked mole rats are long-lived mammals and exhibit markedly decreased signs of spontaneous tumorigenesis during aging and remarkable resistance to hypoxia. In this project, we will identify novel mechanisms that control skin repair after injury and resistance to scar formation in naked mole rats. The generated outputs on this project will provide a platform for their translation into clinics and will promote the development of novel therapeutic interventions, which hopefully could serve as new paradigm for management of skin wound healing and prevention of scar formation.