PDGFRB Signaling in Progressive Skin Disease

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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.