Regulation of Macrophage Activation and Inflammation in Scleroderma

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 DESCRIPTION (provided by applicant): Scleroderma is an autoimmune disease associated with vascular injury, fibrosis, and inflammation. 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 NFκB. NFκB is a master regulator of pro-inflammatory cytokines associated with disease activity in scleroderma. We hypothesize that aberrant regulation of miR-125b in scleroderma MØs leads to enhanced activation of NFκB and pro-inflammatory cytokine production. The goal of this proposal is to determine how activation of NFκB is dysregulated in scleroderma macrophages and to evaluate how modulation of miR-125b alters inflammation associated with this disease. We propose to test the following hypotheses: 1. That NFκB activation differs between MØs derived from scleroderma patients vs. healthy controls. Activation of NFκB 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 NFκB signaling complex. 2. That aberrant expression of miR-125b results in inappropriate activation of NFκB in scleroderma MØs. Our studies have shown that miR-125b enhances expression of κB-Ras2, a negative regulator of NFκB signaling. Aberrant expression of miR-125b has been reported in scleroderma patients. We will assess how aberrant expression of miR-125b in MØs derived from scleroderma patients affects NFκB activation and pro-inflammatory cytokine production.