Mechanisms of Macrophage Activation and Function in Scleroderma

描述（由申请人提供）：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，这表明雌二醇可能与疾病的发生和/或进展有关。目前还没有治愈硬皮病的方法，目前的治疗方法也很有限。由于缺乏对硬皮病病理生理学的了解，硬皮病治疗的进展一直受到阻碍。我们最近报道了在硬皮病患者中异常表达的microRNA miR-125b调节NF-KB的激活。NF-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NF-KB和促炎活性增强。我们建议测试以下假设：NF-KB细胞因子的产生。本提案的目的是确定硬皮病巨噬细胞的激活如何失调，并评估miR-125b的调节如何改变与该疾病相关的炎症1。来自硬皮病患者和健康对照者MØs的NF-KB激活不同。NF-KB的激活有助于硬皮病特征的促炎细胞因子的产生。实验目的是阐明对NF-KB信号复合物的转录激活、DNA结合活性和成分定位的影响。2. miR-125b的异常表达导致硬皮病中NF-KB的不适当激活MØs。我们的研究表明，miR-125b抑制NF-KB信号的负调节因子κB-Ras2的表达。在硬皮病患者中已经报道了miR-125b的异常表达。我们将评估来自硬皮病患者的miR-125b inMØs异常表达如何影响NF-KB激活和促炎细胞因子的产生。3. 与健康对照相比，雌二醇在硬皮病MØs中差异调节miR-125b表达和NFkB激活。这一目的将阐明雌二醇在硬皮病MØs中调控miR-125b如何影响NFkB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.