Function of Desmoglein 1/Pemphigus Foliaceus Antigen

描述（由申请人提供）：桥粒钙粘蛋白是细胞间的黏附分子，对表皮完整性至关重要。在人类表皮表达的7种桥粒体钙粘蛋白中，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强调了Dsg1在维持基底上层粘附方面的重要性，但上一个资助期的数据表明，Dsg1也参与信号介质促进终末分化。这项工作的目的是确定Dsg1如何转运到膜上正确执行其粘附和信号功能，并确定Dsg1介导的信号传导支架如何促进分化。我们假设Dsg1在物理和功能上通过丝裂原活化蛋白激酶（MAPK）和Rho GTPase信号传导开关与基底上分化的启动相耦合。我们将在体外2D和3D器官型培养以及体内人/小鼠异种移植物中使用成像，生物化学和遗传干扰，并通过分析Dsg1突变患者的材料来补充这些研究，以实现以下目标：1)确定Dsg1从内质网输出并通过kinesin和dynein家族的正、负端定向微管马达以及Dsg1相关的接头复合物PX-RICS/14-3-3转运到质膜的机制；2)确定Dsg1如何通过其相关蛋白Erbin抑制有丝分裂原活化蛋白激酶（MAPK）信号传导，促进表皮分化；3)确定Dsg1及其相关蛋白Erbin如何调节rhogtpase依赖的信号通路，促进肌动蛋白重塑，控制细胞形状，调节表皮分化所需的血清反应因子（SRF）介导的转录程序。阐明细胞结构支架如何编排化学信号以促进分化将对治疗皮肤疾病至关重要，因为这些途径被钙粘蛋白基因缺陷、自身抗体或细菌病原体破坏。

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. PUBLIC HEALTH RELEVANCE: This project aims to understand how sticky molecules on the surface of skin cells facilitate the formation of cell sheets to provide an essential skin barrier covering the surface of the body. The studies focus on new functions for these molecules, beyond their role in cell coherence, that control normal tissue development and disease processes. These new pathways are predicted to provide novel therapeutic targets for people with inherited, autoimmune and infectious diseases of the skin.