Epidermal polarization: the desmosomal cadherin desmoglein 1 regulates tissue mechanics and barrier function

表皮极化：桥粒钙粘蛋白桥粒糖蛋白 1 调节组织力学和屏障功能

• 批准号: 9904494
• 负责人: Joshua Allen Broussard
• 金额: $ 8.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904494
• 关键词: 3-Dimensional; Ablation; Actins; Actomyosin; Adhesives; Affect; Apical; Architecture; Area; Atomic Force Microscopy; Atopic Dermatitis; Autoimmune Process; Bacterial Toxins; Basal Cell; Biochemical; Biological Assay; Body Fluids; Cadherins; Cell Proliferation; Cell Shape; Cell physiology; Cells; Cellular Morphology; Chemicals; Cytoskeleton; Data; Defect; Desmosomes; Development; Disease; EMS1 gene; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermis; Epithelial; Epithelium; ErbB Receptor Family Protein; Etiology; Exhibits; Family; Fluorescence; Future; Growth; Health; Heart; Hereditary Disease; Human; Intermediate Filaments; Ions; Lasers; Link; Measures; Mechanical Stress; Mechanics; Mediating; Membrane; Membrane Proteins; Molecular; Movement; Normal tissue morphology; Organelles; Patients; Pattern; Play; Population; Prevalence; Process; Property; Proteins; Psoriasis; Receptor Protein-Tyrosine Kinases; Regulation; Role; Shapes; Signal Transduction; Signaling Molecule; Simple Epithelium; Skin; Spectrum Analysis; Stratification; Stratified Epithelium; Stratum Basale; Stratum Granulosum; Structure; Surface; System; Testing; Tight Junctions; Time; Tissues; Work; apical membrane; basolateral membrane; desmoglein 1; human model; insight; intestinal epithelium; loss of function; mechanical properties; member; molecular marker; mouse model; polymerization; prevent; protein complex; protein expression; receptor; self-renewal; skin barrier; skin disorder; src-Family Kinases; stem cells; wound healing

Cells within all types of epithelia are polarized such that they have distinct domains at their lower and upper regions. For example, in simple epithelia, which consist of a single layer of cells, there are specialized protein complexes near their apical surface that are essential for holding cells together, limiting the passage of molecules and ions through the space between cells, and stopping the movement of membrane proteins between the apical and basolateral membranes. These structures coordinate with cytoskeletal networks to generate contractile forces that are essential in regulating tissue growth, shape, movement, and barrier establishment. Multilayer epithelial tissues, like the epidermis of the skin, are also polarized, but across many cell layers. How these patterns emerge in the epidermis and how they regulate normal tissue functions are not fully understood. This study will focus on the cadherin desmoglein 1 (Dsg1), which is a part of the desmosome, a cell-cell adhesive organelle. Dsg1 is a disease target involved in autoimmune, bacterial toxin-mediated, and inherited diseases and is only expressed in multilayer epithelia. The amount of Dsg1 present in each of the layers of the skin is patterned, with very little protein in the lowest layer and increasing amounts toward the outer layers. This suggests that the functional overlay of patterned Dsg1 onto the baseline machinery found in simple epithelia led to new mechanisms to increase tissue complexity. Preliminary studies indicate that there is a region under high tension in the outermost living layers of the epidermis. Moreover, loss of Dsg1 resulted in a shift in the localization of this high-tension region. It is known that skin is under tension, and that tension contributes to the growth of epidermal tissue as well as to the process of wound healing. In Aim 1 of this proposal, we will use laser ablation and atomic force microscopy to test the role of Dsg1 in regulating epidermal tissue mechanics (tension and stiffness). I hypothesize this occurs through Dsg1 integrating with modulators of the actin cytoskeleton, known regulators of cell forces. Chemical signaling platforms are also patterned in the epidermis, including members of the epidermal growth factor receptor (ErbB) family. The best-known member, epidermal growth factor receptor (EGFR), plays an important role in regulating cell proliferation in the basal layer of the epidermis. However, the functions of other members in the skin are not well known. Preliminary data show that ErbB2 is located in the uppermost living layers of the epidermis, where tight junctions are formed. Tight junctions are an integral part of the epidermal barrier, preventing loss of body fluids and entrance of foreign substances. Dsg1 regulates the total amount and the activity of ErbB2, and together Dsg1 and ErbB2 regulate tight junction proteins. Aim 2 of this proposal will ascertain the mechanism by which Dsg1 affects ErbB2, and the extent to which these proteins work together to regulate the formation and function of the epidermal barrier. Future work will examine the effects of Dsg1-mediated mechanics on ErbB2 activity and barrier function, linking Aims 1 and 2. I propose that Dsg1 integrates mechanical and chemical signals to control the polarized architecture and function of the epidermis.

所有类型上皮内的细胞都是极化的，使得它们在其下部和上部具有不同的结构域。 地区例如，在由单层细胞组成的简单上皮细胞中， 复合物靠近它们的顶端表面，对于将细胞保持在一起至关重要，限制分子通过 和离子通过细胞之间的空间，并停止顶端之间的膜蛋白的运动， 和基底外侧膜。这些结构与细胞骨架网络协调以产生收缩性收缩。 在调节组织生长、形状、运动和屏障建立中必不可少的力。多层 上皮组织（如皮肤的表皮）也是极化的，但跨越许多细胞层。如何将这些 模式出现在表皮中，并且它们如何调节正常组织功能尚未完全了解。这 研究将集中在钙粘蛋白桥粒芯糖蛋白1（Dsg 1），它是桥粒的一部分，桥粒是细胞与细胞之间的粘合剂 细胞器Dsg1是一种涉及自身免疫性、细菌毒素介导的和遗传性疾病的疾病靶标 并且仅在多层上皮中表达。皮肤各层中存在的Dsg1的量为 图案化，在最低层中具有非常少的蛋白质，并且朝向外层增加量。这 表明在简单上皮细胞中发现的模式化Dsg1在基线机制上的功能覆盖导致了 to new新mechanisms机制to increase增加tissue组织complex复杂性.初步研究表明，有一个地区， 表皮最外层的张力。此外，Dsg1的缺失导致了定位的改变， 这个高度紧张的地区。众所周知，皮肤处于张力下，并且张力有助于皮肤的生长。 表皮组织以及伤口愈合的过程。在本提案的目标1中，我们将使用激光烧蚀 和原子力显微镜来测试Dsg1在调节表皮组织力学（张力和张力）中的作用。 刚度）。我假设这是通过Dsg1与肌动蛋白细胞骨架的调节剂整合而发生的， 细胞力的调节器。化学信号平台也在表皮中形成图案，包括 表皮生长因子受体（ErbB）家族。最著名的成员表皮生长因子受体 表皮生长因子受体（EGFR）在调节表皮基底层细胞增殖中起重要作用。但 皮肤中其他成员的功能还不清楚。初步数据显示，ErbB2位于 表皮的最上面的活层，在那里形成紧密连接。紧密连接是 表皮屏障，防止体液流失和异物进入。Dsg1调节总量 Dsg1和ErbB2共同调节紧密连接蛋白。目标2 该提案将确定Dsg1影响ErbB2的机制，以及这些蛋白质的作用程度 共同调节表皮屏障的形成和功能。未来的工作将研究 Dsg1介导ErbB2活性和屏障功能的机制，将目标1和2联系起来。我建议Dsg1 整合机械和化学信号来控制表皮的极化结构和功能。