Function of Desmoglein 1/Pemphigus Foliaceus Antigen

桥粒芯糖蛋白 1/天疱疮叶状疱疹抗原的功能

• 批准号: 8704714
• 负责人: Kathleen Janee Green
• 金额: $ 46.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704714
• 关键词: Actins; Address; Adhesions; Adhesives; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Bacterial Toxins; Binding; Biochemistry; Body Surface; Cadherins; Cell Adhesion Molecules; Cell Shape; Cell membrane; Cell-Cell Adhesion; Cells; Cellular Morphology; Chemicals; Complement; Complex; Coupled; Cues; Cutaneous; Cytoplasmic Tail; Data; Defect; Development; Disease; Disease Pathway; Dynein ATPase; Employee Strikes; Endoplasmic Reticulum; Epidermis; Family; Funding; Gene Expression; Genes; Genetic; Goals; Golgi Apparatus; Hair; Homeostasis; Human; Image; In Vitro; Infectious Skin Diseases; Inherited; Keratoderma; Kinesin; Knockout Mice; Mediating; Mediator of activation protein; Membrane; Microtubules; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphogenesis; Morphology; Motor; Mus; Mutation; Normal tissue morphology; Pathway interactions; Patients; Pattern; Plasma; Process; Proteins; Ras/Raf; Role; Scaffolding Protein; Serum Response Factor; Signal Transduction; Skin; Stratified Epithelium; Stratum Basale; Surface; Syndrome; Testing; Work; Xenograft procedure; desmoglein 1; disease-causing mutation; dynein light chain; in vivo; keratinocyte; member; new therapeutic target; pathogen; programs; rho; rho GTP-Binding Proteins; scaffold; skin disorder; trafficking

DESCRIPTION (provided by applicant): The desmosomal cadherins are cell-cell adhesion molecules that are essential for epidermal integrity. Of the seven desmosomal cadherins expressed in human epidermis, desmoglein 1 (Dsg1) is a particularly prominent disease target. While the existence of inherited, autoimmune and bacterial toxin-mediated skin disease underscores Dsg1's importance in maintaining adhesion in the suprabasal layers, data from the last funding period demonstrate that Dsg1 also engages signaling mediators to promote terminal differentiation. The objective of this work is to identify how Dsg1 is transported to membranes to correctly perform its adhesion and signaling functions, and to determine how Dsg1-mediated signaling scaffolds promote differentiation. We hypothesize that Dsg1 is physically and functionally coupled to the initiation of the suprabasal differentiation through mitogen activated protein kinase (MAPK) and Rho GTPase signaling switches. We will use imaging, biochemistry and genetic interference in vitro in 2D and 3D organotypic cultures and in vivo in human/mouse xenografts, and complement these studies with analysis of material from patients with Dsg1 mutations, to address the following aims: 1) Determine the mechanism of Dsg1 export from the endoplasmic reticulum and transport to the plasma membrane through plus and minus end-directed microtubule motors in the kinesin and dynein families as well as the Dsg1-associated adaptor complex PX-RICS/14-3-3, 2) Determine how Dsg1 dampens mitogen activated protein kinase (MAPK) signaling through its associated protein Erbin to promote epidermal differentiation, and test the importance of this pathway in striate palmar plantar keratoderma (SPPK), and 3) Determine how Dsg1 and its associated protein Erbin regulate RhoGTPase-dependent signaling to promote actin remodeling, control cell shape and regulate serum response factor (SRF)-mediated transcriptional programs necessary for epidermal differentiation. Elucidating how cytoarchitectural scaffolds choreograph chemical signaling to promote differentiation will be essential for treating skin diseases where these pathways are undermined through cadherin gene defects, autoantibodies or bacterial pathogens.

描述(申请人提供)：桥粒钙粘附素是细胞间的黏附分子，对表皮的完整性是必不可少的。在人类表皮表达的7种桥粒钙粘附素中，桥粒蛋白1(DSG1)是一个特别突出的疾病靶点。虽然遗传性、自身免疫性和细菌毒素介导的皮肤病的存在突显了DSG1的S在维持超基底层黏附方面的重要性，但上一次资助期间的数据显示，DSG1也参与了促进终末分化的信号媒介。这项工作的目的是确定DSG1是如何被转运到细胞膜上以正确地执行其黏附和信号功能，并确定DSG1介导的信号支架如何促进分化。我们假设DSG1通过丝裂原活化蛋白激酶(MAPK)和Rho GTPase信号开关在物理和功能上与启动超基础分化有关。我们将在2D和3D器官培养以及人/鼠异种移植的体内应用成像、生物化学和遗传干预，并用来自DSG1突变患者的材料分析来补充这些研究，以解决以下目标：1)确定DSG1从内质网输出并通过驱动蛋白和动力蛋白家族正负末端导向的微管马达运输到质膜的机制，以及DSG1相关的适配器复合体PX-RICS/14-3-3，2)确定DSG1如何通过其相关的蛋白Erbin抑制丝裂原激活的蛋白激酶(MAPK)信号以促进表皮分化以及3)确定DSG1及其相关蛋白Erbin如何调节RhoGTPase依赖的信号以促进肌动蛋白重塑、控制细胞形状和调节血清反应因子(SRF)介导的表皮分化所必需的转录程序。阐明细胞结构支架如何编排化学信号以促进分化，对于治疗皮肤病至关重要，这些途径通过钙粘素基因缺陷、自身抗体或细菌病原体破坏。