# Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2024 · $569,126

## Abstract

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.

## Key facts

- **NIH application ID:** 10915633
- **Project number:** 5R01AR081883-02
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** ANDREW P. KOWALCZYK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $569,126
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915633

## Citation

> US National Institutes of Health, RePORTER application 10915633, Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris (5R01AR081883-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10915633. Licensed CC0.

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