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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.

项目总结/文摘