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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR060780-04
Application #
8731067
Study Section
Special Emphasis Panel (ZAR1-MLB)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$293,439
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Ziemek, Jessica; Man, Ada; Hinchcliff, Monique et al. (2016) The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis. Rheumatology (Oxford) 55:911-7
Nazari, Banafsheh; Rice, Lisa M; Stifano, Giuseppina et al. (2016) Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90. Am J Pathol 186:2650-64
Johnson, Michael E; Grassetti, Andrew V; Taroni, Jaclyn N et al. (2016) Stress granules and RNA processing bodies are novel autoantibody targets in systemic sclerosis. Arthritis Res Ther 18:27
Rice, Lisa M; Stifano, Giuseppina; Ziemek, Jessica et al. (2016) Local skin gene expression reflects both local and systemic skin disease in patients with systemic sclerosis. Rheumatology (Oxford) 55:377-9
Martyanov, Viktor; Whitfield, Michael L (2016) Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data. Curr Opin Rheumatol 28:83-8
Christmann, Romy B; Wooten, Alicia; Sampaio-Barros, Percival et al. (2016) miR-155 in the progression of lung fibrosis in systemic sclerosis. Arthritis Res Ther 18:155
Rice, Lisa M; Padilla, Cristina M; McLaughlin, Sarah R et al. (2015) Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 125:2795-807
Salazar, Gloria A; Assassi, Shervin; Wigley, Fredrick et al. (2015) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum 44:680-6
Mathes, Allison L; Rice, Lisa; Affandi, Alsya J et al. (2015) CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin. Exp Dermatol 24:133-9
Johnson, Michael E; Pioli, Patricia A; Whitfield, Michael L (2015) Gene expression profiling offers insights into the role of innate immune signaling in SSc. Semin Immunopathol 37:501-9

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