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Effects of miR-21 and miR-155 inhibition in SLE

miR-21 和 miR-155 抑制对 SLE 的影响

基本信息

批准号：
8698491
负责人：
MARIANTHI KIRIAKIDOU
金额：
$ 3.26万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698491
关键词：
Affect African American Age Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Apoptosis Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Cell Differentiation process Cell Survival Cell physiology Cells Cessation of life Chronic Clinical Trials Complex DNA Data Deposition Developmental Process Disease Employee Strikes Environmental Risk Factor Excision Experimental Designs Failure Female Fibroblasts Functional RNA Gene Expression General Population Genetic Hispanics Human Hyperactive behavior Immune Tolerance Immune system Immunoglobulins Immunologics In Vitro Interstitial Lung Diseases Kidney Kidney Diseases Kidney Failure Link Lung Lung diseases Lupus Lupus Nephritis Lymphocyte Methodology MicroRNAs Modality Modeling Monoclonal Antibodies Multicenter Studies Mus Nephritis Organ Organ failure Outcome Pathway interactions Patients Peripheral Plasma Cells Pneumonia Process Production RNA Race Replacement Therapy Reporting Risk Role Self Tolerance Sjogren&apos s Syndrome Splenomegaly Susceptibility Gene Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte Therapeutic Therapeutic Intervention Time Tissues Translations Woman belimumab cohort disease phenotype ethnic minority population high risk human disease immunoregulation in vivo male mortality mouse model novel novel therapeutics outcome forecast reproductive research study sex systemic autoimmune disease therapeutic target young woman

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by production and survival of autoreactive antibodies and deposition of immune complexes to various tissues, leading to organ damage. Lupus affects primarily women of reproductive age, with a female to male ratio of 9:1. Mortality in SLE is increased compared to the general population. Higher risk of death is associated with female sex, younger age, shorter SLE duration and African American race. Studies have shown that SLE is more severe among African American, Hispanic and women of other ethnic minorities. Over the last two decades, lupus mortality rates increased by 67.8% among African American women. Results of studies have suggested that this may be related to worse renal involvement and outcome in African American patients. Renal and other severe SLE manifestations respond poorly to current therapeutic modalities and often require replacement therapy. microRNAs (miRNAs) regulate a plethora of normal cellular and developmental processes and their aberrant expression and function is linked to human disease. miRNAs are aberrantly expressed in human and mouse SLE lymphocytes, however their specific function in lupus is poorly understood. We study the expression and function of miRNAs in SLE mouse models and our general hypothesis is that several miRNAs regulate pathways that contribute to the disordered immunoregulation in lupus. Our long-term objective is to characterize and interfere with miRNA-regulated pathways that are common in mouse and human SLE and to investigate the potential of miRNA inhibition as a novel therapeutic direction in lupus. Our preliminary studies showed that LNA antimiRs can be used to efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and that inhibition of a miR-21 using such compounds ameliorates the autoimmune disease phenotype of the B6.Sle123 model. Using the same novel methodology, we propose to study the effect of LNA antimiR inhibition in two of the most severe SLE manifestations: renal and lung disease. With experiments described in Aim I we will study the effect of in vivo miR-21 and miR-155 inhibition on renal disease manifestations in two mouse models of SLE, which recapitulate two different histological classes of human SLE nephritis. With experiments described in Aim II we will examine the effect of in vivo and in vitro miR-21 inhibition on interstitial lung disease in SLE using a mouse model and primary lung fibroblasts from SLE patients.

描述（由申请人提供）：系统性红斑狼疮（SLE, lupus）是一种慢性全身性自身免疫性疾病，其特征是自身反应性抗体的产生和生存以及免疫复合物沉积到各种组织，导致器官损伤。狼疮主要影响育龄妇女，男女比例为9:1。与一般人群相比，SLE患者的死亡率有所增加。较高的死亡风险与女性、年轻、SLE病程较短和非裔美国人种族有关。研究表明，SLE在非裔美国人、西班牙裔和其他少数民族女性中更为严重。在过去的二十年里，非裔美国妇女的狼疮死亡率上升了67.8%。研究结果表明，这可能与非裔美国患者肾脏受累和预后较差有关。肾脏和其他严重SLE表现对目前的治疗方式反应不佳，通常需要替代治疗。microRNAs （miRNAs）调节大量正常细胞和发育过程，其异常表达和功能与人类疾病有关。mirna在人和小鼠SLE淋巴细胞中异常表达，但其在狼疮中的具体功能尚不清楚。我们研究了狼疮小鼠模型中mirna的表达和功能，我们的一般假设是，几种mirna调节了狼疮免疫调节紊乱的途径。我们的长期目标是表征和干扰小鼠和人类SLE中常见的miRNA调控通路，并研究miRNA抑制作为狼疮新治疗方向的潜力。我们的初步研究表明，在体内，LNA antimiRs可用于有效拮抗外周淋巴细胞中的内源性mirna，并且使用此类化合物抑制miR-21可改善B6的自身免疫性疾病表型。Sle123模型。使用相同的新方法，我们建议研究LNA抗ir抑制在两种最严重的SLE表现中的作用：肾脏和肺部疾病。通过Aim I中描述的实验，我们将研究体内miR-21和miR-155抑制对两种SLE小鼠模型肾脏疾病表现的影响，这两种模型概括了人类SLE肾炎的两种不同组织学类型。在Aim II中描述的实验中，我们将使用小鼠模型和SLE患者的原代肺成纤维细胞来研究体内和体外miR-21抑制对SLE间质性肺病的影响。