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

基本信息

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
项目类别：
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

项目摘要

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.

所有类型上皮的细胞都是极化的，因此它们的下部和上部都有不同的域地区。例如，在由单层细胞组成的简单上皮中，有专门的蛋白质其顶部表面附近的复合物对于将细胞固定在一起至关重要，限制了分子的通过离子穿过细胞之间的空间，并停止顶端之间的膜蛋白的运动和基底膜。这些结构与细胞骨架网络协调以产生收缩在调节组织生长，形状，运动和障碍物中至关重要的力。多层上皮组织，例如皮肤的表皮，也是极化的，但在许多细胞层上。这些如何表皮中出现模式及其如何调节正常组织功能。这研究将侧重于钙粘蛋白脱木蛋白1（DSG1），这是脱糖体的一部分，一种细胞 - 细胞粘合剂细胞器。 DSG1是涉及自身免疫性，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。皮肤每一层中存在的DSG1量是图案化，最低层的蛋白质很少，对外层的含量增加。这建议在简单的上皮LED中发现的基线机械的功能叠加层提高组织复杂性的新机制。初步研究表明，有一个地区表皮最外层生命层的张力。此外，DSG1的丢失导致本地化的变化这个高压区域。众所周知，皮肤处于紧张状态，紧张有助于表皮组织以及伤口愈合的过程。在本提案的目标1中，我们将使用激光消融和原子力显微镜测试DSG1在调节表皮组织中的作用（张力和张力和刚性）。我假设这是通过与肌动蛋白细胞骨架的调节剂集成的DSG1发生的，已知细胞力的调节剂。化学信号平台也在表皮中图案化，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（EGFR），在调节表皮基底层的细胞增殖中起重要作用。但是，皮肤中其他成员的功能尚不清楚。初步数据显示ERBB2位于表皮的最高生活层，在那里形成紧密的连接处。紧密连接是不可或缺的一部分表皮屏障，防止体液损失和异物入口。 DSG1调节总数 ERBB2的数量和活性，DSG1和ERBB2一起调节紧密连接蛋白。目标2 建议将确定DSG1影响ERBB2的机制以及这些蛋白质的工作程度共同调节表皮屏障的形成和功能。未来的工作将检查 DSG1介导的ERBB2活性和屏障功能的力学，链接目标1和2。我建议DSG1 整合机械和化学信号以控制表皮的极化结构和功能。