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The epidermis forms our protective barrier that is essential for body survival. Skin desquamation depends on the tightly regulated activity of kallikrein-related peptidases (KLKs). KLK5 is hypothesized to initiate a proteolytic cascade that results in corneocyte shedding and stratum corneum renewal. Epidermal KLK5 hyperactivation has been reported in severe ichthyoses such as the Peeling Skin Disease (PSD, or Peeling Skin Syndrome-type B) caused by mutations of the corneodesmosin (Cdsn) gene. Cdsn-/- mice recapitulate the disease although, as in many cases of invalidation of late epidermis differentiation expressed genes, they die soon after birth. We will use our Klk5-/- mice to generate the Klk5-/-Cdsn-/- mice and answer whether ablation of Klk5 is sufficient to reduce proteolytic activity and stabilize the desmosomes. We will use degradomics and transcriptomics in patient and mouse models to define the role of proteolysis as a major pathogenesis mechanism for PSD. This will also reveal the presence of alternative proteolytic pathways that may be involved and could be targeted in concert with KLK5. In addition, the significance of KLK5 inhibition in the reversal of PSD symptoms will also be tested in new organotypic cultures. The ultimate outcome of the proposal is to answer whether invalidation of KLK5 in vivo is sufficient to restore the phenotype of PSD and identify other potential enzymes that should be targeted for the development of the first targeted therapeutic approach. These findings could also be beneficial to treat other ichthyoses or inflammatory skin disease