Mechanoregulation of the epidermal immune response: the role of desmoglein 1

表皮免疫反应的机械调节：桥粒芯糖蛋白 1 的作用

• 批准号: 10314801
• 负责人: Quinn Roth-Carter
• 金额: $ 6.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314801
• 关键词: Adhesions; Affect; Area; Atopic Dermatitis; Cadherins; Cell Culture Techniques; Cell membrane; Cells; Cytoskeleton; Data; Defect; Dermatitis; Desmosomes; Development; Disease; Down-Regulation; ERBB2 gene; Elbow; Environment; Epidermal Growth Factor Receptor; Epidermis; Exposure to; Extensor; Flexor; Gene Expression; Gene Proteins; Genetic; Homeostasis; Hypersensitivity; Immune response; Infectious Skin Diseases; Inflammation; Inflammatory; Inflammatory Response; Intercellular Junctions; Intermediate Filaments; Knockout Mice; Knowledge; Lead; Lesion; Link; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK3 gene; Mechanical Stress; Mechanics; Mediating; Metabolic; Molecular; Molecular Structure; Mutation; Organism; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Play; Proteins; Psoriasis; Reactive Oxygen Species; Recurrence; Reporting; Role; STAT3 gene; Serum Response Factor; Signal Pathway; Signal Transduction; Skin; Stratified Epithelium; Stress; Syndrome; Testing; Tissues; Vertebrates; Work; biochemical tools; cell behavior; chronic inflammatory disease; cytokine; desmoglein 1; effective therapy; experience; improved; insight; keratinocyte; keratinocyte differentiation; knock-down; protein degradation; response; scaffold; sensor; skin barrier; skin disorder; tool; transcriptome; wasting

Project Summary The epidermis of the skin provides an essential barrier between the organism and the environment. Disruption of the epidermal barrier is associated with chronic inflammatory diseases such as psoriasis and atopic dermatitis. Affected areas in patients with these diseases are frequently distributed in regions that experience higher amounts of mechanical stress, such as the extensor areas in psoriasis and flexor regions in atopic dermatitis. The underlying basis of sensitivity to mechanical stress in these diseases is unknown. Desmosomes are intercellular junctions that are critical for both formation of the barrier and for providing mechanical strength to the epidermis and are abundant in tissues that experience large amounts of mechanical stress. The desmosomal cadherin Desmoglein 1 (Dsg1) is only expressed in stratified epithelium such as the epidermis and is critical for proper epidermal development and function. Mutations in Dsg1 causes severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome, a chronic inflammatory disease associated with recurrent skin infections, abnormal epidermal differentiation and loss of adhesion between keratinocytes. Barrier defects in these patients may explain some of the inflammation present in the skin; however, isolated keratinocytes continue to express increased proinflammatory cytokine levels in cell culture. Knockdown of Dsg1 in normal primary keratinocytes also causes an increase in proinflammatory cytokine expression. These data raise the possibility that Dsg1 contributes to inflammatory responses. Other evidence indicates that Dsg1 may act as a stress sensor. Dsg1 is downregulated by several types of environmental stress, including exposure to UV. Preliminary data show that Dsg1 is downregulated in differentiated keratinocytes exposed to mechanical stress. Mechanical stress also increases expression of proinflammatory cytokines in keratinocytes, many of which overlap with those increased in keratinocytes after knockdown of Dsg1. This proposal will test the hypothesis that Dsg1 is a mechanical stress sensor and regulates epidermal inflammatory responses. Aim 1 seeks to identify the mechanism by which Dsg1 regulates cytokine expression in keratinocytes. This aim will also test the extent to which the downregulation of Dsg1 in response to mechanical stress regulates increased cytokine expression. Aim 2 will determine the molecular mechanism by which mechanical stress downregulates Dsg1 levels in keratinocytes. Preliminary data indicate that Dsg1 is also downregulated in response to oxidative stress, and the extent to which increased oxidative stress induced by mechanical insult downregulates Dsg1 will be tested. Increasing our knowledge of mechanisms by which mechanical stress drives inflammatory responses will improve our understanding of diseases such as psoriasis and atopic dermatitis, and potentially identify new targets for developing more effective therapies.

项目摘要 皮肤的表皮提供了生物体和环境之间的基本屏障。中断 表皮屏障的破坏与慢性炎性疾病如银屑病和特应性皮炎有关。 这些疾病患者的受影响地区通常分布在经历较高风险的地区。 机械应力的量，如银屑病的伸肌区域和特应性皮炎的屈肌区域。 这些疾病对机械应力敏感性的基础尚不清楚。桥粒是 细胞间连接对于屏障的形成和提供机械强度都是至关重要的， 表皮和大量存在于经受大量机械应力的组织中。桥粒 钙粘蛋白桥粒芯糖蛋白1（Dsg 1）仅在复层上皮如表皮中表达，并且对于 正常的表皮发育和功能。Dsg 1的突变会导致严重的皮炎，多种过敏， 代谢性消耗（SAM）综合征，一种与复发性皮肤感染相关的慢性炎性疾病， 异常表皮分化和角质形成细胞之间的粘附丧失。这些患者的屏障缺陷 可以解释皮肤中存在的一些炎症;然而，分离的角质形成细胞继续表达 细胞培养物中促炎细胞因子水平增加。正常原代角质形成细胞中Dsg 1的敲低 也导致促炎细胞因子表达的增加。这些数据提出了Dsg 1 有助于炎症反应。其他证据表明，Dsg 1可能作为一个压力传感器。DSG 1是 下调的几种类型的环境压力，包括暴露于紫外线。初步数据显示， Dsg 1在暴露于机械应力的分化角质形成细胞中下调。机械应力也 增加角质形成细胞中促炎细胞因子的表达，其中许多与那些增加的细胞因子重叠。 在角质形成细胞中，Dsg 1被敲低后。这个提议将检验Dsg 1是一个机械的 压力传感器和调节表皮炎症反应。目标1旨在通过以下方式确定机制： 其中Dsg 1调节角质形成细胞中的细胞因子表达。这一目标也将检验 Dsg 1对机械应力的响应下调调节了细胞因子表达的增加。目标2将 确定机械应力下调角质形成细胞中Dsg 1水平的分子机制。 初步数据表明，Dsg 1在氧化应激反应中也被下调，并且在多大程度上， 将测试由机械损伤诱导的增加的氧化应激下调Dsg 1。增加我们 机械应力驱动炎症反应的机制的知识将提高我们的 了解银屑病和特应性皮炎等疾病，并可能确定新的靶点， 开发更有效的治疗方法