Systemic sclerosis (SSc) is a rare, complex rheumatic disease involving multiple organ systems with a frequently fatal outcome. It remains perhaps the most difficult rheumatic disease to manage, with limited effective therapies. One of the greatest impediments to finding new treatments is the heterogeneity of patient presentation and disease progression. Clinical markers are unable to predict onset and/or progression of the major complications, such as progressive fibrotic skin disease, pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), each seen in a minority of SSc patients. Identification of biomarkers permitting early recognition of these complications would potentially permit more targeted therapies, but also provide enriched """"""""at risk"""""""" populations for enrolling in therapeutic trials. We focus in this Center of Research Translation on identifying biomarkers of SSc complications and progression. Empowered by a very large SSc clinical population, we propose careful clinical evaluations (Clinical-Core B), coupled with powerful molecular approaches (Microarray-Core C) to identify skin, serum and peripheral blood mononuclear cell (PBMC) disease biomarkers. We supplement this with strong translational studies into pathogenesis, probing in highly interactive projects fibrosis, vascular inflammation and the stress response in SSc. In Project 1, Dr. Lafyatis, Center Director, will investigate biomarkers in the skin predicting progressive skin disease. This project will also validate a recently identified 4-gene biomarker and test this biomarker as an outcome measure for a novel, short-duration, open-label trial of a high affinity, pan-anti-TGFp antibody. In project 2, Dr. Farber will identify biomarkers predicting the onset of PAH. In overlap with Project 1, these will be compared to biomarkers of ILD and further explored in a new model of PAH, the adiponectin-/- mouse. In Project 3 Dr. Trojanowska will extend data showing expression of HLA-B35, associated with SSc-PAH, induces a stress/unfolded protein response (UPR), and that stress response genes, ATF4 and ATF6 are more broadly upregulated in SSc. She will define the stress/UPR response in PBMCs and endothelial cells, and in overlap with Projects 1 and 2 investigate how the stress response relates to SSc disease activity.

Public Health Relevance

Systemic sclerosis is a poorly understood and relatively rare, but frequently fatal illness, involving widespread scarring and vascular disease. This project is designed to coordinate multiple scientists and clinicians to accelerate understanding of the disease process through highly interactive patient-oriented studies into markers of disease activity, investigation of pathogenesis and trial of a novel therapeutic.

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 (M1))
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Wang, Yan Z
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Grzegorzewska, Agnieszka P; Seta, Francesca; Han, Rong et al. (2017) Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7:41605
Makino, Katsunari; Makino, Tomoko; Stawski, Lukasz et al. (2017) Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis. J Invest Dermatol 137:1671-1681
Fleury, Michelle; Belkina, Anna C; Proctor, Elizabeth A et al. (2017) Increased expression and modulated regulatory activity of co-inhibitory receptors PD-1, TIGIT and TIM-3 in lymphocytes of systemic sclerosis patients. Arthritis Rheumatol :
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
Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi et al. (2017) Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. J Invest Dermatol 137:631-640
Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor et al. (2017) A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med 9:27
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
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
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

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