权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Characterization of microRNA-regulated signaling pathways in mouse SLE

小鼠 SLE 中 microRNA 调节信号通路的表征

基本信息

批准号：
8261693
负责人：
MARIANTHI KIRIAKIDOU
金额：
$ 8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8261693
关键词：
3&apos Untranslated Regions Affect Affinity Antibody Formation Antigen-Antibody Complex Antisense Oligonucleotides Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Basic Science Cell physiology Chronic Clinical Clinical Research Clinical Trials Complex Congenic Mice Core Protein Deposition Development Discipline Disease Failure Functional RNA Future Gene Expression Gene Expression Regulation Genes Genetic Glomerulonephritis Goals Hepatitis Human Hyperactive behavior Immune system In Vitro Individual Kidney Diseases Knowledge Lupus Lupus Nephritis Lymphocyte Mediating Messenger RNA Methods MicroRNAs Modality Modeling Molecular Mus Nephritis Organ Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Physiological Processes Play Process Production Proteins RNA Sequences RNA-Induced Silencing Complex Regulatory Pathway Research Role Self Tolerance Serological Severities Signal Pathway Small RNA Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte Techniques Time Tissues Translational Repression Translational Research autoreactivity base human disease immunoregulation in vivo insight interest mRNA Decay mouse model new therapeutic target novel novel strategies novel therapeutics public health relevance response systemic autoimmune disease therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by auto reactivity of B and T cells, production of autoantibodies and tissue deposition of immune complexes, resulting in organ damage. Disordered immunoregulation in SLE occurs in a genetic background involving lupus susceptibility genes. Hyperactivity and abnormal responses of B cells is at the center of SLE pathogenesis and leads to increased production of autoantibodies, failure of self tolerance mechanisms and inadequate clearing of immune complexes. microRNAs (miRNAs) emerged over the last decade as a conserved class of non-coding RNAs that regulates gene expression. Accumulating evidence underscores the importance of this pathway, whose tentacles control regulatory circuits in development, in normal physiologic processes and in disease state. Current evidence supports a key role for miRNAs in the development and function of the immune system and emerging evidence underscores the importance of this regulatory pathway in autoimmunity. However, the signaling pathways regulated by miRNAs in SLE remain largely unknown. Research in our lab focuses on the function of miRNAs in the tri-congenic mouse model B6.Sle123. Autoimmune disease in B6.Sle123 is characterized by autoantibodies, lymphosplenomegaly and glomerulonephritis, strongly resembling human lupus. We studied the expression of miRNAs in B6.Sle123 lymphocytes, at different time points in the course of twelve months, while the autoimmune disease of B6.Sle123 mice progresses from mild to severe. We demonstrated that expression of a set of miRNAs positively correlates with development and severity of severe lupus manifestations, such as kidney disease. Current therapies available for SLE are toxic and they are not targeting lupus-specific disordered mechanisms. The proposed research focuses on identifying miRNA-dependent signaling pathways that are uniquely affected in a mouse model of lupus, in which disease manifestations and disordered mechanisms overlap with those in human SLE. In our studies we will employ novel in vivo experimental methods combined with standard in vitro techniques. Our ultimate plan is to broaden our knowledge and understanding of miRNA function in lupus and to identify potential novel therapeutic targets in SLE. PUBLIC HEALTH RELEVANCE: Results from basic, translational and clinical research underscore the importance of gene regulation mediated by microRNAs (miRNAs). miRNAs control pathways important in normal development and normal cellular functions, however they also play instrumental roles in disease mechanisms. Although current evidence supports a critical role for miRNAs in the development and function of the immune system, very little is known about the function of miRNAs in autoimmune diseases and in particular in Systemic Lupus Erythematosus (SLE). We propose to identify and characterize the molecular pathways that are regulated by miRNAs in lupus, using a genetic tricongenic mouse lupus model that recapitulates many seroligcal and clinical manifestations of human disease. Our long term goal is to identify disordered molecular pathways in lupus, which could potentially serve as novel, disease specific, therapeutic targets. We foresee that results of the studies described in this proposal will be of considerable interest to a broad spectrum of biomedical disciplines

描述(申请人提供)：系统性红斑狼疮(SLE，狼疮)是一种慢性系统性自身免疫性疾病，其特征是B和T细胞的自身反应，产生自身抗体和免疫复合物的组织沉积，导致器官损害。系统性红斑狼疮的免疫调节紊乱发生在涉及狼疮易感基因的遗传背景中。B细胞的过度活跃和异常反应是SLE发病机制的核心，导致自身抗体的产生增加，自身耐受机制失效，免疫复合物清除不足。MicroRNAs(MiRNAs)是在过去十年中出现的一类保守的非编码RNA，调节基因表达。越来越多的证据强调了这一途径的重要性，它的触角控制着发育、正常生理过程和疾病状态中的调节电路。目前的证据支持miRNAs在免疫系统的发育和功能中发挥关键作用，新出现的证据强调了这一调控途径在自身免疫中的重要性。然而，在系统性红斑狼疮中，miRNAs调控的信号通路在很大程度上仍不清楚。本实验室的研究重点是miRNAs在B6.Sle123三基因小鼠模型中的功能。B6中的自身免疫性疾病Sle123的特征是自身抗体、淋巴脾肿大和肾小球肾炎，与人类狼疮非常相似。在B6.Sle123小鼠自身免疫性疾病由轻到重的过程中，我们研究了12个月内不同时间点B6.Sle123小鼠淋巴细胞中miRNAs的表达。我们证明了一组miRNAs的表达与严重狼疮表现的发展和严重程度呈正相关，如肾脏疾病。目前治疗系统性红斑狼疮的方法是有毒的，它们并不针对狼疮特有的紊乱机制。这项拟议的研究集中于识别在狼疮小鼠模型中唯一受影响的miRNA依赖的信号通路，在该模型中，疾病表现和紊乱的机制与人类SLE的疾病表现和紊乱机制重叠。在我们的研究中，我们将采用新颖的体内实验方法和标准的体外技术相结合。我们的最终计划是扩大我们对狼疮miRNA功能的了解和理解，并确定SLE潜在的新治疗靶点。公共卫生相关性：基础、翻译和临床研究的结果强调了由microRNAs(MiRNAs)介导的基因调控的重要性。MiRNAs控制着正常发育和正常细胞功能的重要途径，但它们在疾病机制中也发挥着重要作用。虽然目前的证据支持miRNAs在免疫系统的发育和功能中发挥关键作用，但对miRNAs在自身免疫性疾病中的功能，特别是在系统性红斑狼疮(SLE)中的功能知之甚少。我们建议使用一个基因三基因的小鼠狼疮模型来鉴定和表征在狼疮中受miRNAs调控的分子通路，该模型概括了人类疾病的许多血清和临床表现。我们的长期目标是确定狼疮中紊乱的分子通路，这可能会成为新的、疾病特异性的治疗靶点。我们预计，这项建议中描述的研究结果将对广泛的生物医学学科产生相当大的兴趣。