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
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Lenna, Stefania; Han, Rong; Trojanowska, Maria (2014) Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life 66:530-7
Arron, Sarah T; Dimon, Michelle T; Li, Zhenghui et al. (2014) High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis. J Invest Dermatol 134:2138-45
Christmann, Romy B; Sampaio-Barros, Percival; Stifano, Giuseppina et al. (2014) Association of Interferon- and transforming growth factor ?-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol 66:714-25
van Bon, Lenny; Affandi, Alsya J; Broen, Jasper et al. (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433-43
Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert et al. (2014) Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol 66:1010-21
Vacca, Alessandra; Meune, Christophe; Gordon, Jessica et al. (2014) Cardiac arrhythmias and conduction defects in systemic sclerosis. Rheumatology (Oxford) 53:1172-7
Gopal, Deepa M; Doldt, Bryan; Finch, Kim et al. (2014) Relation of novel echocardiographic measures to invasive hemodynamic assessment in scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 66:1386-94
Christmann, Romy B; Mathes, Allison; Affandi, Alsya J et al. (2013) Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor *. Arthritis Rheum 65:1335-46
Hinchcliff, Monique; Huang, Chiang-Ching; Wood, Tammara A et al. (2013) Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol 133:1979-89

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