Regulation of Macrophage Activation and Inflammation in Scleroderma

 描述(申请人提供)：硬皮病是一种与血管损伤、纤维化和炎症相关的自身免疫性疾病。目前还没有治愈硬皮病的已知方法，目前的治疗方法也很有限。由于缺乏对硬皮病基础的病理生理学知识，防治硬皮病的疗法的开发进展受到了阻碍。我们最近报道，在硬皮病患者中异常表达的微小RNA miR-125b调节NFκB的激活。NFκB是与硬皮病疾病活动相关的促炎细胞因子的主要调节因子。我们推测，在S硬皮病中，miR-125b的异常调节导致了核因子κB的激活和促炎细胞因子的产生。该方案的目的是确定硬皮病巨噬细胞中核因子κB的激活是如何失调的，并评估miR-125b的调节如何改变与这种疾病相关的炎症。我们建议检验以下假设：1.硬皮病患者和健康对照组的核因子κB活性不同于S硬皮病患者。核因子κB的激活参与了硬皮病特有的促炎细胞因子的产生。这一目的的实验将阐明对转录激活、dna结合活性和核因子κB信号复合体成分的定位的影响。2.miR-125b的异常表达导致了核因子κB在S硬皮病中的异常激活，我们的研究表明miR-125b增强了κB-RAS2的表达，Ras2是NFκB信号的负调控因子。已有报道在硬皮病患者中存在miR-125b的异常表达。我们将评估硬皮病患者来源的MäS中miR-125b的异常表达如何影响核因子κB的激活和促炎细胞因子的产生。

 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.