Clinical-Translational Studies in Skin, Lung, and Vascular Complications in Systemic Sclerosis

The overall goal of this Center of Research Translation is to utilize biomarker tools and other translational research observations to discover new therapies for patients with systemic sclerosis (SSc). This goal can be broken down into four intermediate objectives: understanding pathogenic pathways through translational studies,

identifying informative biomarkers for SSc complications, applying bioinformatics and systems biology approaches to interpret translational and biomarker data, and developing novel targeted therapeutics. Among current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of

SSc pathogenesis, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models. The University of Pittsburgh School of Medicine stands in a unique position for informative translational studies into SSc due to special resources and intellectual talent. It has very large, longitudinal clinical-biological

SSc repositories in rheumatology and pulmonary divisions; it has the only large national experience in single cell studies in both SSc skin and lungs; it has a strong experience in studying lung proteomics; it has pulmonary experts in modeling lung disease using in vitro precision cut lung slices and ex vivo lung perfusion; it has a

highly sophisticated program studying pediatric localized scleroderma, as well as pediatric SSc; it has an experienced and innovative systems biology group; and it has a vigorous drug discovery platform. In Project 1 investigators will expand preliminary observations using single cell RNA-seq, to understand the transcription

factors (TFs) associated with myofibroblast differentiation and discover latent factors/cytokine mediating macrophage-fibroblast interaction in SSc and pediatric LS. In Project 2 investigators will examine the genomic and proteomic landscape of patients with SSc-associated interstitial lung disease. Project 2 will also screen

and carry out preclinical studies of Smad3 translocation inhibitors using precision cut lung slices. In Project 3 investigators will study altered platelet energetics and utilize 18F-fluoroglutamine PET imaging to understand the role of metabolic reprogramming and glutaminolysis in SSc-associated pulmonary arterial hypertension.

Project aims will be supported by two resource cores: a Clinical and Biospecimen Core and a Systems Biology Core. The former will include collecting comprehensive clinical data, acquiring skin biopsies and lung explant tissue, and preparing precision cut lung slices. The latter will use a broad range of bioinformatics tools, including

novel methods for detecting stereospecific TF binding sites, and for discovering latent factors mediating cell- cell interactions in scRNA-seq/multiome datasets. The Systems Biology Core will also synthesize proteomic and genomic data in project 2, and integrate data from each project and across projects to develop models for

common molecular pathways associated with different disease manifestations. The focus of each of the projects on different SSc clinical manifestations, mediators of disease, and drug inhibitors will provide a rich, highly collaborative environment for fundamental discovery within bridging project topics and core resources.