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: 7809799
• 负责人: Kathleen Janee Green
• 金额: $ 46.43万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809799
• 关键词: Ablation; Adhesions; Adhesives; Biology; Cadherins; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Deposition; Desmosomes; Employment; Epidermis; Epithelial; Epithelial Cells; Equipment; Equipment and Supplies; Extracellular Matrix; Funding; Goals; Human; Human Resources; Human body; Integrins; Intercellular Junctions; Mediating; Morphogenesis; National Research Service Awards; Normal tissue morphology; Null Lymphocytes; Pathologic Processes; Pathway interactions; Play; Postdoctoral Fellow; Proteomics; Public Health; Regulation; Role; Secure; Signal Transduction; Skin; Substrate Interaction; Surface; Testing; Tissues; Work; Wound Healing; armadillo proteins; cell behavior; cell motility; desmocollin; desmoglein; desmoglein 1; insight; keratinocyte; novel; parent grant; plakoglobin; skin disorder

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.

描述（由申请人提供）：桥粒糖蛋白（Dsgs）是Ca 2+依赖性粘附分子，与桥粒柯林斯结合构成细胞间连接的粘附核心（称为桥粒）。这一竞争性修订补充建议扩大我们的母基金的范围，其主要目标是阐明桥粒芯糖蛋白1的功能，桥粒芯糖蛋白1首先表达为细胞开始分化并集中在表皮的浅层。期间 在这些研究过程中，犰狳蛋白斑珠蛋白（PG）已经成为一种重要的 能够协调其粘附依赖性和非依赖性的Dsg 1相关分子 活动PG缺失细胞基质接触材料的蛋白质组学分析 揭示了整合素和基质谱的巨大变化，这可以解释以前的研究。 观察到单个PG缺陷细胞运动性的改变。细胞-细胞和细胞-基质粘附 在正常组织形态发生过程中以及在上皮细胞生长过程中， 伤口愈合过程中的重塑我们认为Dsg 1在这一过程中起着核心作用。 通过其伴侣PG协调，加强完整组织中的细胞-细胞粘附， 调节具有有限细胞间接触的重塑上皮细胞的运动性。为了验证这一 我们提出：1）确定Dsg 1是否充当调节ECM的“变阻器 以PG依赖的方式，研究整合素沉积、整合素介导的角质形成细胞-基质相互作用和细胞运动性，以及2）为了检验PG通过以下方式抑制角质形成细胞运动性的假设： 通过Src调节细胞骨架和ECM重塑。总的来说，这项工作将有助于 更好地了解桥粒钙粘蛋白生物学的一个新方面--它们的功能串扰 与细胞-ECM连接分子。与母公司补助金的预付款结合起来， 这些研究将提供对涉及此的表皮中的正常和病理过程的深入了解。 新的信号轴所要求的资金将提供一个就业的延长 博士后研究员在他的NRSA和获得独立资金之间的间隙， 以及资金，以支持雇用新的技术人员和小型设备，以帮助加快 建议研究的速度。 公共卫生解放：桥粒芯糖蛋白是在人体许多细胞表面发现的“粘性”分子。在人类皮肤细胞中发现的桥粒芯糖蛋白的功能性消融导致严重的皮肤病。本申请中的研究将提供资金来支持人员、物资和设备探索一种新的途径，桥粒核心蛋白通过该途径调节细胞行为，取代其已知的将细胞粘附在一起的作用，包括调节皮肤伤口期间的细胞运动性 治愈