Mechanisms of Macrophage Activation and Function in Scleroderma

硬皮病巨噬细胞激活和功能的机制

• 批准号: 8898494
• 负责人: Patricia A. Pioli
• 金额: $ 8.1万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898494
• 关键词: Affect; Attenuated; Autoimmune Diseases; Binding; Blood Vessels; Cells; Characteristics; Complex; Cytokine Gene; DNA Binding; Development; Diagnosis; Disease; Disease Progression; Ensure; Estradiol; Estrogens; Etiology; Fibrosis; Frequencies; Functional RNA; Functional disorder; Gene Expression; Goals; Gonadal Steroid Hormones; Health; Hormones; Human; Immune; Immune Cell Activation; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Macrophage Activation; Messenger RNA; MicroRNAs; NF-kappa B; Nuclear; Onset of illness; Pathogenesis; Pathway interactions; Patients; Play; Production; Receptor Signaling; Regulation; Reporting; Research; Role; Scleroderma; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Steroid Receptors; Systemic Scleroderma; Testing; Therapeutic; Time; Transcriptional Activation; Tumor Necrosis Factor-alpha; Untranslated Regions; Vascular Diseases; Woman; alternative treatment; combat; cytokine; macrophage; men; microbial; monocyte; novel; pulmonary arterial hypertension; research study; response; therapeutic target; therapy development; treatment strategy; vascular inflammation

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.

描述（由适用提供）：硬皮病是一种与血管损伤，纤维化和感染相关的自身免疫性疾病。女性的硬皮病比男性多7-12倍，这表明雌二醇可能参与疾病的发展和/或进展。没有已知的硬皮病治疗方法，并且当前的治疗是有限的。缺乏对这种疾病的病理生理学的了解，阻碍了对抗硬皮病的疗法发展的进展。我们最近报道说，在硬皮病患者中异常表达的miRORNA miR-125b调节NF-KB的激活。 NF-KB是与硬皮病疾病活性相关的促炎细胞因子的主要调节剂。我们假设在硬皮病中miR-125b的异常调节导致NF-KB和促炎的激活增强。我们建议检验以下假设：NF-KB细胞因子的产生。该提案的目的是确定在硬皮病巨噬细胞中的激活失调，并评估miR-125b的调节如何改变与这种疾病相关的感染1。 NF-KB的激活有助于硬皮病的促炎细胞因子生产特征。此目标中的实验将阐明对NF-KB信号复合物的成分的转录激活，DNA结合活性和定位的影响。 2。miR-125b的异常表达导致在硬皮病Møs中适当激活NF-KB。我们的研究表明，miR-125b抑制了NF-KB信号传导的负调节剂的表达。在硬皮病患者中，已经报道了miR-125b的异常表达。我们将评估源自硬皮病患者的miR-125bInmø的异常表达如何影响NF-KB的激活和促炎性细胞因子的产生。 3。雌二醇对硬化症Møs与健康对照组中的miR-125b表达和NFKB激活进行了不同的调节。这个目标将阐明rad二醇对硬化症møs中miR-125b的调节如何影响NFKB的激活和炎症。