Scleroderma is a heterogeneous disease of unknown etiology that results in cutaneous fibrosis, autoimmunity, internal organ dysfunction, and microvascular obliteration. Despite over 15,000 Pubmed citations on the disease, there is limited understanding of the molecular mechanisms at play in scleroderma. This indicates that a new approach is needed. In this core, our preliminary data establish that high- throughput genomic approaches can generate insights into the pathological processes driving skin fibrosis in patients with systemic sclerosis with diffuse scleroderma. Analysis of the spectrum of gene expression in skin biopsies demonstrates our ability to quantitatively separate patients into distinct groups based on their gene expression patterns alone. These groupings are independent of disease duration, but instead reflect different fundamental biology, similar to what has been found in the molecular subtypes of breast and lung tumors. We show that the distinct groups identified by gene expression can be mapped to definable clinical covariates. The Pi's experience and the optimized sample processing protocols, and data analysis methods will be utilized for this core. The goals are to (1) hybridize skin biopsies and PBMC samples from patients with scleroderma and normal controls as they arrive at Dartmouth, (2) to analyze the resulting data for biomarkers the predict disease activity and (3) to generate hypotheses regarding the molecular mechanisms underlying scleroderma that could ultimately be tested by more cell biological methods. The core will also employ pilot RNAseq experiments using ultra-high throughput sequencing methods.

Public Health Relevance

(See Instructions): Scleroderma is a major health concern. High throughput gene expression has identified subsets in scleroderma that are driven by fundamentally different pathways. The core will provide the ability to subset patients as a component of this CORT proposal and each subset will likely respond differently to therapy. It will also allow us to test if specific pathways investigated in each project are deregulated in patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1-MLB)
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Boston University
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Stifano, Giuseppina; Sornasse, Thierry; Rice, Lisa M et al. (2018) Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol 70:912-919
Franks, Jennifer M; Cai, Guoshuai; Whitfield, Michael L (2018) Feature specific quantile normalization enables cross-platform classification of molecular subtypes using gene expression data. Bioinformatics 34:1868-1874
Apostolidis, Sokratis A; Stifano, Giuseppina; Tabib, Tracy et al. (2018) Single Cell RNA Sequencing Identifies HSPG2 and APLNR as Markers of Endothelial Cell Injury in Systemic Sclerosis Skin. Front Immunol 9:2191
Fleury, Michelle; Belkina, Anna C; Proctor, Elizabeth A et al. (2018) Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis. Arthritis Rheumatol 70:566-577
Moll, Matthew; Christmann, Romy B; Zhang, Yuqing et al. (2018) Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease. J Scleroderma Relat Disord 3:242-248
Meiners, Silke; Evankovich, John; Mallampalli, Rama K (2018) The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis. Transl Res 198:17-28
Rice, Lisa M; Mantero, Julio C; Stratton, Eric A et al. (2018) Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis. Arthritis Res Ther 20:185
Rice, Lisa M; Mantero, Julio C; Stifano, Giuseppina et al. (2017) A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin. J Invest Dermatol 137:62-70
Taroni, Jaclyn N; Mahoney, J Matthew; Whitfield, Michael L (2017) The mechanistic implications of gene expression studies in SSc: Insights from Systems Biology. Curr Treatm Opt Rheumatol 3:181-192
Lafyatis, Robert; Mantero, Julio C; Gordon, Jessica et al. (2017) Inhibition of ?-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82. J Invest Dermatol 137:2473-2483

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