权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris

皮肤起疱病寻常型天疱疮中的角质形成细胞粘附和信号传导

基本信息

批准号：
10732360
负责人：
ANDREW P. KOWALCZYK
金额：
$ 60.45万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10732360
关键词：
3-Dimensional Adhesions Adhesives Antibodies Architecture Atomic Force Microscopy Autoantibodies Autoimmune B cell therapy Binding Biology Bulla Cadherins Cell Adhesion Cell Communication Cell-Cell Adhesion Cells Clathrin Communicable Diseases Complex Cryoelectron Microscopy Cultured Cells Desmosomes Development Disease Disease Progression Endocytosis Endoplasmic Reticulum Epidermis Epithelium Epitope Mapping Exposure to Foundations Homeostasis Imaging technology Immunoglobulin G Immunosuppressive Agents Infectious Skin Diseases Inflammatory Response Inherited Intercellular Junctions Life MAP Kinase Gene Mediating Membrane Microdomains Modeling Molecular Monoclonal Antibodies Mucous Membrane Outcome Study Pathway interactions Patients Pemphigus Pemphigus Vulgaris Peripheral Play Protein Dynamics Proteins Rare Diseases Regulation Resolution Risk Role Series Shapes Signal Induction Signal Pathway Signal Transduction Skin Sorting Stress Testing Tissues Transcript Tubular formation Vesicle cellular imaging design desmoglein III disorder risk endoplasmic reticulum stress experimental study imaging approach improved insight keratinocyte live cell imaging molecular dynamics new therapeutic target novel novel therapeutics optical imaging p38 Mitogen Activated Protein Kinase particle patient safety response skin barrier skin disorder therapeutic target

项目摘要

Project Summary/Abstract Desmosomes are adhesive intercellular junctions that play critical roles in epidermal homeostasis by mediating robust cell-cell adhesion and by modulating signaling pathways that regulate epidermal differentiation. The importance of desmosomes is highlighted by numerous autoimmune and inherited skin diseases that compromise desmosome function and cause epidermal fragility. These diseases include pemphigus vulgaris (PV), a severe autoimmune epidermal blistering disease caused by autoantibodies (IgG) directed against the desmosomal cadherin desmoglein-3 (Dsg3). The precise mechanism by which PV IgG disrupt desmosome adhesion and trigger signaling pathways associated with the loss of adhesion are not well understood. This limitation has hindered the development of new therapies that can spare or eliminate the need for immunosuppressive treatments which can pose risks for patient safety. In the current proposal, we outline a series of cutting edge imaging approaches that will resolve with previously unachievable detail precisely how PV IgG disrupt adhesion. Aim 1 studies will determine how pemphigus IgG disrupt desmosome dynamics, architecture, and function using cryo-EM, live cell imaging, and molecular dynamics simulations. In Aim 2, we focus on how keratinocytes respond to pemphigus IgG and the role of Ca2+ signaling and endoplasmic reticulum stress pathways in the endocytosis of desmosomal proteins and in the inflammatory responses associated with desmosome disruption in both cultured cells and patient tissues. The outcome of these studies will produce fundamentally new conceptual models for desmosome regulation and will form a foundation for the treatment of skin diseases associated with loss of desmosome adhesion.

项目摘要/摘要桥粒是一种黏附的细胞间连接，通过以下方式在表皮内稳态中发挥关键作用通过调节调节表皮的信号通路来调节强健的细胞-细胞黏附差异化。大量的自身免疫性和遗传性皮肤突出了桥粒的重要性。损害桥粒功能并导致表皮脆弱的疾病。这些疾病包括寻常型天疱疮是由自身抗体引起的一种严重的自身免疫性表皮水疱病。针对桥粒钙粘附素桥粒糖蛋白-3(Dsg3)。PV-Ig G感染的确切机制破坏桥粒黏附和触发与黏附丧失相关的信号通路不是很好明白了。这一局限性阻碍了新疗法的发展，这些疗法可以避免或消除需要免疫抑制治疗，这可能会对患者的安全构成风险。在目前的提案中，我们勾勒出一系列前沿成像方法，这些方法将解决以前无法实现的细节 PV免疫球蛋白是如何破坏粘连的。目标1研究将确定天疱疮免疫球蛋白如何破坏桥粒使用低温EM、活细胞成像和分子动力学模拟的动力学、体系结构和功能。在……里面目的2，我们重点研究角质形成细胞对天疱疮免疫球蛋白的反应，以及钙信号和免疫球蛋白的作用。内质网应激途径在桥粒蛋白内吞和炎性反应中的作用在培养细胞和患者组织中与桥粒破坏相关的反应。其结果是这些研究将从根本上产生桥粒调控的概念模型，并将形成为治疗与桥粒粘连丧失相关的皮肤病奠定基础。