Scleroderma is an autoimmune disease associated with vascular injury, fibrosis, and inflammation. Women develop scleroderma 7-12 times more often than men, suggesting estradiol may be involved in disease development and/or progression. There is no known cure for scleroderma and current treatments are limited. Progress in the development of therapies to combat scleroderma has been hampered by a lack of knowledge of the pathophysiology that underlies this disease. We recently reported that miR-125b, a microRNA aberrantly expressed in scleroderma patients, regulates activation of NF-KB. NF-KB is a master regulator of pro-inflammatory cytokines associated with disease activity in scleroderma. We hypothesize that aberrant regulation of miR-125b in scleroderma leads to enhanced activation of NF-KB and pro-inflammatory. We propose to test the following hypotheses: NF-KB cytokine production. The goal of this proposal is to determine how activation is dysregulated in scleroderma macrophages and to evaluate how modulation of miR-125b alters inflammation associated with this disease 1. That NF-KB activation differs between Ms derived from scleroderma patients vs. healthy controls. Activation of NF-KB contributes to pro-inflammatory cytokine production characteristic of scleroderma. Experiments in this aim will elucidate effects on transcriptional activation, DNA binding activity and localization of components of the NF-KB signaling complex. 2. That aberrant expression of miR-125b results in inappropriate activation of NF-KB in scleroderma Ms. Our studies have shown that miR-125b inhibits expression of ?B-Ras2, a negative regulator of NF-KB signaling. Aberrant expression of miR-125b has been reported in scleroderma patients. We will assess how aberrant expression of miR-125b inMs derived from scleroderma patients affects NF-KB activation and pro-inflammatory cytokine production. 3. That estradiol differentially modulates miR-125b expression and NFkB activation in scleroderma Ms vs. healthy controls.
This aim will elucidate how estradiol regulation of miR-125b in scleroderma Ms affects NFkB activation and inflammation.

Public Health Relevance

Scleroderma is an autoimmune disease characterized by immune cell activation, inflammation, vascular injury, and fibrosis. It affects women 7-12 times more frequently than men, yet relatively little is known about the role sex hormones, particularly estrogen;play in disease development and/or progression. The studies in this proposal will identify key signaling pathways that are dysregulated in scleroderma and will elucidate the role of estrogen in the regulation of these pathways

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZAR1)
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Mancini, Marie
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Dartmouth College
Obstetrics & Gynecology
Schools of Medicine
United States
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Yeager, Mark P; Pioli, Patricia A; Collins, Jane et al. (2016) Glucocorticoids enhance the in vivo migratory response of human monocytes. Brain Behav Immun 54:86-94