Function of Desmoglein 1/Pemphigus Foliaceus Antigen

描述(申请人提供)：桥粒蛋白(DGs)是一种依赖于钙离子的黏附分子，它与桥粒结合构成细胞间连接的黏附核心，称为桥粒。这一竞争性的修订补充建议扩大我们的父母赠款的范围，其主要目标是阐明桥粒芯糖蛋白1的功能，它首先在细胞开始分化时表达，并集中在表皮的浅层。在.期间 在这些研究过程中，蜈蚣蛋白(PG)已成为一种重要的 DSG1相关分子能够协调其黏附依赖和非黏附 活动。PG-空细胞来源的细胞-底物接触材料的蛋白质组学分析 揭示了整合素和基质图谱的戏剧性变化，这可以解释之前 观察单个PG缺陷细胞的运动性改变。细胞-细胞和细胞-基质黏附 在正常组织形态发生过程中以及在上皮细胞形成过程中 在伤口愈合过程中发生的重塑。我们认为DSG1在这一过程中起着核心作用 通过其伙伴PG进行协调，加强完整组织中细胞与细胞的黏附，以及 调节细胞间接触有限的重塑上皮细胞的运动性。为了测试这一点 我们建议：1)确定DSG1是否是调节细胞外基质的变阻器 PG依赖的沉积、整合素介导的角质形成细胞-底物相互作用和细胞运动，以及2)验证PG通过以下方式抑制角质形成细胞运动的假设 通过Src调节细胞骨架和细胞外基质重塑。总而言之，这项工作将有助于 更好地理解桥粒钙粘附素生物学的一个新方面--它们的功能串扰 通过细胞-细胞外基质连接分子。与母公司赠款的预付款相结合，这些 研究将深入了解与此相关的表皮的正常和病理过程。 新颖的信号轴。所要求的资金将为一名 博士后在他的NRSA和获得独立资金之间的间歇期，因为 以及支持雇用新技术人员和小型设备的资金，以帮助加快 建议研究的进度。 公共卫生报道：桥粒蛋白是一种“粘性”分子，存在于人体许多细胞表面。对人体皮肤细胞中的桥粒蛋白进行功能性消融会导致严重的皮肤病。这项应用中的研究将提供资金支持人员、用品和设备，以探索一种新的途径，通过该途径，桥粒甘氨酸调节细胞行为，取代它们在粘连细胞方面的已知作用，包括调节皮肤创伤期间的细胞运动。 治愈。

DESCRIPTION (provided by applicant): Desmogleins (Dsgs) are Ca2+dependent adhesion molecules that partner with desmocollins to make up the adhesive core of intercellular junctions called desmosomes. This competing revision supplement proposes to expand the scope of our parent grant, a major goal of which was to elucidate the function of desmoglein 1, which is first expressed as cells begin to differentiate and becomes concentrated in the superficial layers of the epidermis. During the course of these studies, the armadillo protein plakoglobin (PG) has emerged as an important Dsg1-associated molecule capable of orchestrating its adhesion-dependent and -independent activities. Proteomics analysis of cell-substrate contact material derived from PG-null cells revealed dramatic alterations in integrin and matrix profiles, which could explain previously observed alterations in motility of single PG-deficient cells. Cell-cell and cell-substrate adhesion is carefully coordinated during normal tissue morphogenesis as well as during epithelial remodeling that occurs in wound healing. We propose that Dsg1 plays a central role in this coordination through its partner PG, strengthening cell-cell adhesion in intact tissues, and regulating motility in remodeling epithelial cells with limited intercellular contact. To test this idea, we propose: 1) To determine whether Dsg1 acts as a "rheostat" to regulate ECM deposition, integrin-mediated keratinocyte cell-substrate interactions and cell motility in a PG-dependent manner, and 2) To test the hypothesis that PG inhibits keratinocyte motility by regulating cytoskeletal and ECM remodeling through Src. Taken together, this work will help to better understand a novel aspect of desmosomal cadherin biology -- their functional cross-talk with cell-ECM junctional molecules. Integrated with advances from the parent grant, these studies will provide insight into normal and pathological processes in epidermis involving this novel signaling axis. The requested funds will provide an extension of employment for a postdoctoral fellow during the hiatus between his NRSA and securing independent funding, as well as funds to support hiring a new technician and small equipment to help accelerate the pace of the proposed studies. PUBLIC HEALTH RELEVENCE: Desmogleins are "sticky" molecules found on the surface of many cells in the human body. Functional ablation of the desmogleins found in human skin cells results in severe skin disease. The studies in this application will provide funds to support personnel, supplies and equipment to explore a novel pathway through which desmogleins regulate cell behaviors that supersede their known roles in sticking cells together, including regulation of cell motility during skin wound healing.