PROJECT SUMMARY / ABSTRACT Ichthyosis describes the dry, scaly skin that results from different genetic disorders that alter different constituents of the skin barrier. In all forms of ichthyosis major changes occur in the quality, quantity and function of the stratum corneum, the soil on which the microbiome grows. Common phenotypic features of the ichthyoses include scaly skin, increased trans-epidermal water loss (TEWL), and reduced stratum corneum water content. However, significant biochemical differences will also exist depending on the genotype of the ichthyosis. In turn, these biochemical differences are likely determinants of the skin microbiome. The goal of our proposal is to understand the effect of the skin microenvironment on microbial colonization and dynamics through the study of monogenic human skin disorders. We will first, compare the skin microbiome of individuals with genetically distinct ichthyoses with healthy individuals, testing the null hypothesis that the skin microbiome in all individuals with ichthyosis is the same, regardless of the genetic cause of their ichthyosis, but will be different from that of healthy skin. We will recruit 10 individuals each from five distinctive genetic diagnoses and 20 gender and age-matched healthy controls. Performing metagenomic shotgun sequencing, we will compare microbial diversity, composition, and microbial biochemical pathways with genotype to identify differences between ichthyotic and healthy skin and between patient cohorts. This will identify microbes that possess metabolic pathways that may be associated with the unique biochemical substrate created by each deficiency. Second, we will correlate the ichthyotic skin microbiome with phenotypic features to determine microbial associations with skin environment, because biochemical differences in the stratum corneum resulting from the different mutations may not be the critical determinant of the microbiome. Therefore, we will test the null hypothesis that the skin microbiome in all individuals with ichthyosis is the same regardless of the underlying biochemical manifestation of their disease, but is dependent on skin characteristics. We will identify correlates such as diversity, composition, and microbial biochemical pathways with phenotypic characteristics, such as lamellar vs. keratodermic scale, inflammation, TEWL defects, temperature, pH from the different patient cohorts and controls. These correlates may explain interactions that are phenotype rather than genotype-specific. This project will provide basic insights into whether the skin microbiome of ichthyotic skin is modified by the biochemical differences in the stratum corneum due to monogenic skin disorders, or if the ichthyotic environment is the dominant determinant of the skin microbiome.