PROJECT SUMMARY Ethnic disparities represent a significant problem in modern dermatology, and additional efforts are required to better understand mechanisms underlying the development of skin diseases in patients with skin of color. Inflammatory skin conditions (acne, atopic dermatitis, hidradenitis suppurativa) represent a group of diseases, which disproportionally impact African American (AA) patients including children. Comparative transcriptome analyses of the skin reveal higher expression of multiple inflammation-related genes in AA healthy individuals compared to non-Hispanic White (NHW) individuals. Regulation of expression of the genes involved in inflammatory skin response occurs at several levels including signaling/transcription factor-mediated and epigenetic mechanisms. Transposable elements (TEs) are repetitive mobile segments of DNA that constitute 44%-55% of mouse or human genomes. Inappropriate TE activation has been implicated in pathogenesis of over 120 human diseases including autoimmune disorders. Most TEs are transcriptionally inactive, while their aberrant activation result in a production of double- stranded (ds) RNA and dsDNA triggering the dsRNA/DNA sensing mechanisms followed by anti-viral immune response. In the epidermis, UV exposure activates transcription of endogenous retroviral sequences. Endogenous retroviruses of the HERV-K and W families are significantly upregulated in psoriatic versus non- lesional skin. However, contribution of TEs to regulation of skin inflammation in AA individuals remain unknown. In this Administrative Supplement application to AR078306-03 grant, we will test a hypothesis that aberrant activation of TEs in epidermal keratinocytes serve as critical determinant driving inflammatory skin response in individuals with understudied skin types, while pharmacological inhibition of the TE transcription with the nucleoside reverse transcriptase inhibitors provides a novel strategy for management of inflammatory skin conditions in these individuals. This hypothesis will be addressed via two Specific Aims: 1. Perform comparative analyses of the landscapes of transposable element expression in human epidermal keratinocytes between understudied skin types and NHW skin and correlate these data with gene expression and patterns of active/repressive covalent DNA/histone modifications. 2. Define the effects of the inhibitors of dsRNA and dsDNA pathways on expression of inflammation- associated genes in epidermal keratinocytes isolated from understudied skin types in 3D skin equivalent culture and in experimental in vitro models of skin inflammation. The generated outputs from this application will provide novel insights into fundamental mechanisms regulating inflammation in understudied human skin types, as well as will promote the development of novel paradigms for management of skin inflammatory responses in humans via modulation of TE activities.

PROJECT NARRATIVE Transposable elements constitute a significant part of the non-coding genome, while their inappropriate activation has been implicated in pathogenesis of over 120 human diseases including autoimmune disorders. In this application, we will address the following questions: 1) Are there any differences in the expression of genome transposable elements between epidermal keratinocytes isolated from the skin of African American, Hispanic and Asian origin and non-Hispanic White origin, 2) Which mechanisms regulate transposable element silencing in keratinocytes of different ethnic groups, and 3) Whether modulation of inflammatory response by nucleoside reverse transcriptase inhibitors might serve as new approach for management of skin inflammatory conditions in individuals with understudied skin types. The generated outputs on this project will provide a platform for translation of these results into clinics and will promote the development of novel therapeutic interventions, which hopefully could serve as new paradigm for management of skin inflammatory conditions in patients with skin of color and their prevention.