Skin Barrier Adaptation

摘要 表皮对恶劣的外部环境提供皮肤屏障功能，是皮肤损伤的主要部位。 维生素D生产。表皮角质形成细胞功能缺陷导致皮肤感染风险增加 和炎症。表皮分化复合体(EDC)编码基因的表达 基因座对表皮功能至关重要，必须适应不同的环境才能进一步确保生存。我们 发现了人类表皮的最新进化。我们报告了最近一次选择性的扫荡， 欧洲人和非洲人表皮中总蛋白(IVL)的表达 人口。我们的发现揭示了人类表皮的功能多样性和适应性 人类迁出非洲。然而，白花蛇舌草蛋白的作用机制及其对功能的影响 适应性表皮功能尚不清楚。在这里，我们的目标是严格理解 IVL调节表皮中维生素D受体(VDR)的功能，这是一种基于我们的研究的新兴范式 活体小鼠和人类种群研究。IVL基因敲除(IVL-/-)小鼠的维生素D受体水平较低 在表皮中的表达导致配体结合的维生素D受体信号的减少和抑制 TSLP介导的炎症反应。这种新发现的IVL-/-小鼠的表型突出了IVL的功能作用 为表皮免疫串扰调制VDR信号，与以前的工作不同，该工作发现总绿色素会 对于皮肤屏障的形成是必不可少的。这一发现意义重大，因为IVL和VDR在 欧洲血统个体的表皮与相对降低的IVL和VDR表达相反 在非洲血统的个体的表皮中。总之，我们在老鼠和人类身上的发现揭示了 IVL/VDR的功能调节轴，构成人类进化选择和多样性的基础 表皮。在这项研究中，我们将检验以下最重要的假设。Involucrin对维生素D的调节 作为人类皮肤多样性基础的适应性表皮功能的受体功能和表皮串扰 和进化论。我们将在以下具体目标中检验这一假设。目标1.确定监管机构 IVL增加的机制。目的2.确定Involucrin介导的维生素调节机制 D受体。目的3.鉴定表皮免疫适应性串扰的包衣蛋白途径。已完成的 AIMS将为IVL/VDR轴功能产生新的知识，这是人类皮肤多样性和 进化论。这一知识将促进针对特定人群皮肤和皮肤的精准医学倡议 对于实现全球皮肤健康至关重要。

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.