Skin Barrier Adaptation

皮肤屏障适应

基本信息

批准号：
10467695
负责人：
Cristina de Guzman Strong
金额：
$ 35.55万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-19 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467695
关键词：
ATAC-seq Africa African African ancestry Agonist Alleles Atopic Dermatitis Binding Biological Assay Biology CD4 Positive T Lymphocytes Cells ChIP-seq Chromatin Complex Defect Development Ensure Environment Epidermis European Evolution Exhibits Flow Cytometry Gene Expression Gene Frequency Genes Genetic Genetic Transcription Geography Goals Haplotypes Health Homeostasis Human IRF1 gene Immune Individual Infectious Skin Diseases Inflammation Inflammatory Knock-out Knowledge Lead Ligands Link Mediating Molecular Mus NFIC gene Out-Migrations Pathway interactions Pharmacology Phenotype Population Precision Health Precision Medicine Initiative Production Proteomics RELA gene Receptor Activation Receptor Signaling Regulation Reporter Reporting Research Risk Risk Factors Role Signal Transduction Signaling Molecule Site Skin TSLP gene Testing Transcription Coactivator Variant Vitamin D Vitamin D3 Receptor Work base casein kinase chromatin immunoprecipitation comparative conditional knockout design dosage human migration human population study in vivo involucrin keratinocyte knock-down knowledge translation loss of function multiple omics receptor expression receptor function response single-cell RNA sequencing skin barrier skin disorder small hairpin RNA transcription factor transcriptome sequencing

项目摘要

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.

抽象的表皮提供针对严酷的外部环境的皮肤屏障功能，是维生素D产生。表皮角质形成细胞功能的缺陷导致皮肤感染的风险增加和炎症。表皮分化复合物（EDC）中编码的基因的表达基因座对于必须适应不同环境以进一步确保生存的表皮功能至关重要。我们在人类表皮中发现了最近的进化。我们报告了最近的选择性扫描以增加与非洲人相反人群。我们的发现揭示了与人类表皮相关的人类表皮的功能多样性和适应人类从非洲迁移。然而自适应表皮功能尚不清楚。在这里，我们旨在严格理解 IVL调节表皮中的维生素D受体（VDR）功能，这是一种基于我们的新兴范例体内小鼠和人口研究。 IVL敲除（IVL - / - ）小鼠表达较低水平的维生素D受体表皮中的表达导致配体结合的维生素D受体信号降低并抑制 TSLP介导的炎症。这种新发现的IVL - / - 小鼠的表型突出了IVL的功能作用调节表皮免疫串扰的VDR信号与以前的工作相反，该作品发现易素蛋白可用于皮肤屏障的发育。这一发现很重要，因为IVL和VDR都在增加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个体的表皮中。我们在老鼠和人类中的发现一起揭示了一个 IVL/VDR的功能调节轴是人类进化选择和多样性的基础表皮。我们将在这项研究中检验以下总体假设。依赖蛋白调节维生素D 受体功能和表皮串扰，用于自适应表皮功能，这是人类皮肤多样性的基础和进化。我们将在以下特定目标中检验这一假设。目标1。确定监管 IVL增加的机制。目标2。确定依赖蛋白介导的维生素调节的机制 D受体。目标3。确定适应性表皮免疫串扰的易素途径。完成 AIMS将为IVL/VDR轴功能产生新知识，该功能是人类皮肤多样性和进化。这些知识将促进精确的医学计划，专为人群特定的皮肤和对于实现全球皮肤健康至关重要。