ABSTRACT The epidermis provides skin barrier function against the harsh external environment and is the primary site of vitamin D production. Deficiencies in epidermal keratinocyte function lead to increased risks for skin infection and inflammation. The expression of genes encoded within the Epidermal Differentiation Complex (EDC) locus is critical for epidermal function that must adapt to different environments to further ensure survival. We discovered recent evolution in the human epidermis. We report a recent selective sweep for increased involucrin (IVL) expression in the epidermis of individuals from European populations in contrast to African populations. Our finding reveals functional diversity and adaptation in the human epidermis associated with human migration out of Africa. Yet the mechanisms for involucrin dosage and the functional impact for adaptive epidermal function are not known. Here we aim to rigorously understand the mechanisms by which IVL modulates Vitamin D receptor (VDR) function in the epidermis, an emerging paradigm based on our in vivo mouse and human population studies. Ivl knockout (Ivl-/-) mice express lower levels of vitamin D receptor expression in the epidermis resulting in decreased ligand-bound vitamin D receptor signaling and dampened Tslp-mediated inflammation. This newly discovered phenotype for Ivl-/- mice highlights a functional role for Ivl to modulate Vdr signaling for epidermal immune crosstalk in contrast to previous work that found involucrin to be dispensable for skin barrier development. This finding is significant as IVL and VDR are both increased in the epidermis of individuals of European ancestry in contrast to relatively decreased IVL and VDR expression in the epidermis of individuals of African ancestry. Together, our discoveries in mice and human reveal a functional regulatory axis for IVL/VDR that underlies the evolutionary selection and diversity of the human epidermis. We will test the following overarching hypothesis in this study. Involucrin modulates vitamin D receptor function and epidermal crosstalk for adaptive epidermal function that underlies human skin diversity and evolution. We will test this hypothesis in the following specific aims. Aim 1. Identify the regulatory mechanisms for increased IVL. Aim 2. Identify the mechanisms for Involucrin-mediated regulation of vitamin D receptor. Aim 3. Identify the involucrin pathway for adaptive epidermal immune crosstalk. Completion of the aims will generate new knowledge for IVL/VDR axis function that underlies human skin diversity and evolution. This knowledge will facilitate precision medicine initiatives designed for population-specific skin and critical for achieving global skin health.

PROJECT NARRATIVE The research will identify the functional mechanisms for adaptive epidermal function. We will gain new knowledge from the proposed work that premised on human skin barrier evolution and a diverse set of skin from different ancestries. The translation of this knowledge will facilitate precision health treatments for inflammatory skin diseases.