Systemic Sclerosis (SSc) is characterized by heterogeneous disease manifestations and variations in disease prSystemic sclerosis (SSc) presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. Heterogeneous disease progression makes it impossible with currently available clinical tools to tell whose skin and internal organ disease is going to progress, and whose is going to stabilize or improve spontaneously. We have recently shown that expression of four genes in the skin correlates highly with the modified Rodnan skin score (MRSS), suggesting that markers for disease progression, predicting future changes in the MRSS, might also be identified with the proper clinical/pathological samples. The major focus of the first aim in this proposal is to identify such biomarkers. We propose two approaches utilizing RNA expression analyses and immunohistochemical studies targeting markers of vascular inflammation and injury. These studies will overlap with studies in Project 2 looking at markers of lung disease and studies in aim 3 looking at vascular inflammation and stress. Biomarkers of disease activity and progression might supplement or, in early phase trials, replace clinical outcome measures, such as the MRSS, potentially permitting short (open label) trials where the skin score would not normally be expected to change significantly. Notably, the potent profibrotic cytokine, transforming growth factor-p (TGF(3) regulates two of the genes in our 4-gene skin biomarker (COMP and THS1). We propose in aim 2 to standardize and validate the performance of this 4-gene biomarker of skin disease, by comparing reproducibility in biopsies repeated in adjacent and contralateral forearm, and by examining the change over short and longer periods of time. Finally, in the third aim we propose a short-term open label trial of the high affinity pan-anti-TGFp antibody, GC1008. We will test the hypothesize that this antibody will rapidly inhibit TGF(3 signature mRNA expression in the 4-gene biomarker, validating utility of the biomarker and providing preliminary proof-of-concept data for a larger clinical trial using this agent.
Systemic sclerosis is a rare scarring disease affecting skin and internal organs frequently leading to death from lung, intestinal or kidney involvement. In this proposal we will identify markers in the blood to better define which patients will progress to have severe complicaitons. We will also carry out a small clinical trial, testing a medication that blocks the most potent regulator in the body of fibrosis (scarring).
|Farina, Antonella; Cirone, Mara; York, Michael et al. (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954-64|
|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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