Mechanisms of Macrophage Activation and Function 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。女性患硬皮病的几率是男性的7-12倍，这表明雌二醇可能参与了疾病的发展和/或进展。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。我们最近报道了一种在硬皮病患者中异常表达的微小RNA miR-125b，它调节着核因子-KB的激活。核因子-KB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。我们假设，硬皮病中miR-125b的异常调节导致核因子-KB的激活和促炎作用的增强。我们建议检验以下假设：核因子-KB细胞因子的产生。本研究的目的是确定硬皮病巨噬细胞的激活是如何失调的，并评估miR-125b的调节如何改变与此疾病相关的炎症1。核因子-KB的激活在硬皮病患者和健康对照组之间存在差异。核因子-kB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-KB信号复合体成分定位的影响。2.miR-125b的异常表达导致了核因子-kB在S硬皮病中的异常激活，我们的研究表明miR-125b抑制了核因子-kB信号负调控因子κB-ras2的表达。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miR-125b的异常表达如何影响核因子-KB的激活和促炎细胞因子的产生。3.S硬皮病患者与正常对照组比较，雌激素对miR-125b表达和NFkB活化的调节作用不同。这一目的将阐明雌激素对硬皮病M？S中miR-125b的调节如何影响NFkB的激活和炎症。

DESCRIPTION (provided by applicant): 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 MØs 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 MØs. Our studies have shown that miR-125b inhibits expression of κB-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 inMØs 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 MØs vs. healthy controls. This aim will elucidate how estradiol regulation of miR-125b in scleroderma MØs affects NFkB activation and inflammation.