# PDGFRB Signaling in Progressive Skin Disease

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $513,700

## Abstract

Project Summary/Abstract
Solving the pathogenesis of rare genetic diseases leads to greater understanding of basic physiology and gene
function. It was recently discovered that gain-of-function mutations in human PDGFRB, encoding platelet-derived
growth factor receptor β (PDGFRβ), unexpectedly associate with syndromic diseases involving the skin. The
phenotypes involve dermal atrophy resembling accelerated aging or, paradoxically, dermal thickening and
fibrosis with keloid-like scarring. These observations raise important questions about functions of PDGFRβ in
the skin, including the target cell types and signaling pathways responsible for disease. Whether different human
PDGFRB mutations cause distinct disease phenotypes is unclear because of limited numbers of patients to date
and lack of appropriate genetic models. Addressing these questions will shed new light on the role of PDGFRβ
in the skin. The objective is to identify PDGFRβ-regulated mechanisms controlling dermal cells and their
contribution to skin disease and physiology. The central hypothesis is that PDGFRβ in dermal fibroblasts controls
the balance of downstream effectors including STATs and AKT, which are critical for the maintenance of healthy
skin and are imbalanced in disease. Aim 1 will use inducible Cre/lox approaches in mice to induce PDGFRβ
activating mutations in fibroblasts or dermal adipocytes, with combinatorial deletion of STAT family members
and STAT target genes to uncover new downstream mediators of dermal fibrosis. Aim 2 will characterize a new
mouse model with a mutation found in Kosaki overgrowth syndrome, and test the hypothesis that AKT activation
is required for overgrowth with progressive loss of dermal adipose tissue. Aim 3 will characterize a new mouse
model with a Penttinen progeroid syndrome mutation, and test the hypothesis that STAT1 is a central mediator
of the progeroid skin phenotype and anti-growth characteristics of mutant fibroblasts. This project draws on the
PI’s expertise in PDGF signaling to resolve the paradoxical consequences of elevated PDGFRβ signaling in skin
disease. The results of this project will develop genetic models of two human diseases, by dissecting the cell
type-specific role of PDGFRβ signaling in dermal fibrosis and dermal adipose tissue atrophy, and by establishing
the conceptual framework of PDGFRβ-STAT signaling in the skin. This information may point to novel therapeutic
strategies for fibrosis and aging in contexts beyond these rare genetic diseases.

## Key facts

- **NIH application ID:** 10771006
- **Project number:** 5R01AR080896-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** LORIN E OLSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $513,700
- **Award type:** 5
- **Project period:** 2023-02-08 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771006

## Citation

> US National Institutes of Health, RePORTER application 10771006, PDGFRB Signaling in Progressive Skin Disease (5R01AR080896-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10771006. Licensed CC0.

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