# Project 1: Systemic Sclerosis Skin Biomarkers & Therapeutics

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $221,464

## Abstract

Currently there remain very limited treatment options for patients with systemic sclerosis (SSc). 
Pharmacodynamic biomarker genes, such as THBS1 and COMP, developed in our previous CORT project, have 
proven valuable for assessing the efficacy of new therapies. Finding prognostic biomarkers is increasingly 
important for deciding which patients to treat with toxic therapies. In addition, genes/proteins associated with 
disease progression (prognostic biomarkers) likely drive disease. We have recently shown that COMP and 
SPP1, and CTGF and SERPINE1 are markers of progressive SSc associated interstitial lung disease (ILD)and 
skin disease, respectively. These genes are expressed by mesenchymal cells and are upregulated in vitro by 
TGFβ. Using single cell RNA-seq, in preliminary results we show transcriptome modules in healthy skin for 
mesenchymal cells, including subsets of pericytes and fibroblasts, and SSc skin identified a distinct 
transcriptome expressed uniquely on myofibroblasts. We propose that one or more of the mesenchymal cell 
types in normal skin are progenitors of myofibroblasts in SSc skin. Genes in this myofibroblast transcriptome 
include ADAM12, ITGA11, as well as biomarkers of SSc skin disease, such as THBS1, COMP, CTGF and 
SERPINE1. Thus, biomarkers of progressive SSc skin disease are expressed mainly by myofibroblasts. ADAM12 
and ITGA11, expressed on cells identified as myofibroblasts, likely regulate the phenotype of these cells, as 
deletion of ITGA11 in mice markedly inhibits myofibroblast accumulation after wounding, and ADAM12 is a 
marker of pericyte progenitors that in mice differentiate into myofibroblasts. Our preliminary data 
support a singular hypothesis of this proposal that select biomarker genes drive differentiation 
of a mesenchymal cell type that is responsible for fibrosis in SSc skin and lungs. We will take 
advantage of unique resources developed in our laboratory to study thousands of single cell transcriptomes in 
skin, combining this with the exceptional access to patients with early diffuse cutaneous SSc provided by the 
UPMC Scleroderma Center. We propose three aims to evaluate this hypothesis. First, we will identify 
biomarkers of progressive fibrosis in SSc skin and SSc-ILD. We will identify and validate prognostic skin 
mRNA biomarkers of dcSSc skin disease and validate serum biomarkers identified using Somascan proteomic 
technology of progressive SSc-ILD. Second, we will investigate single cell transcriptomes and the relationship 
between dermal mesenchymal cells in normal and SSc skin. Further, we will compare quantitative and 
qualitative changes of the transcriptomes of mesenchymal cells from patients with dcSSc to healthy controls 
and identify profibrotic fibroblast and myofibroblast progenitors. Third, we will study the roles of TGFβ, 
ADAM12 and ITGA11 on regulating myofibroblast differentiation by testing the kinetics of TGFβ on inducing 
the myofibroblast transcriptome, by identify...

## Key facts

- **NIH application ID:** 10022107
- **Project number:** 5P50AR060780-09
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ROBERT A. LAFYATIS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,464
- **Award type:** 5
- **Project period:** 2011-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022107

## Citation

> US National Institutes of Health, RePORTER application 10022107, Project 1: Systemic Sclerosis Skin Biomarkers & Therapeutics (5P50AR060780-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10022107. Licensed CC0.

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