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The Role of miR-17~92 in Autoimmune Diseases

miR-17~92在自身免疫性疾病中的作用

基本信息

批准号：
8640880
负责人：
Changchun Xiao
金额：
$ 42.3万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640880
关键词：
Apoptosis Applications Grants Autoimmune Diseases Autoimmunity B-Lymphocytes Bioinformatics Biological Biological Process Biology Bone Marrow CD19 gene Cell Differentiation process Cells Clonal Deletion Code Communities Development Diagnostic Disease Down-Regulation Epigenetic Process Exhibits Future Gene Amplification Gene Targeting Genes Genetic Genomics Goals High-Throughput Nucleotide Sequencing Human Immune Tolerance Immune response Immune system Immunoprecipitation Individual Light Lymphocyte Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Mammalian Cell Mammals Mediating Messenger RNA Methods MicroRNAs Modeling Molecular Monitor Mus Mutation Outcome Pathway interactions Patients Pattern Pilot Projects Play Production Proteins Proteomics Publishing Repression Research Role Subfamily lentivirinae Superantigens T-Lymphocyte Technology Therapeutic Intervention Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Translational Repression Translations Untranslated Regions Work anergy anti-IgM cohort crosslink human disease innovation insight mRNA Decay mouse development mouse model protein expression public health relevance receptor recombinase reconstitution research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) have recently emerged as a major class of trans-factors that regulate expression of protein coding genes through their 3'UTRs, thereby controlling a diverse range of biological processes including cell differentiation, proliferation, and apoptosis. miRNAs pair with mRNAs of their target genes and the usual consequence is the downregulation of protein expression by translational repression, mRNA cleavage, or promotion of mRNA decay. Hundreds of miRNAs, many of them evolutionarily conserved, have been identified in mammals, and a fraction of these molecules exhibit highly specific, regulated expression patterns in the immune system. Genetic studies from us and other groups have demonstrated that miRNAs play critical roles in lymphocyte development, immune responses, and lymphomagenesis. However, little is known about the roles of miRNAs in autoimmune diseases. A large amount of genetic and epigenetic alterations in miRNA coding genes have been found in human patients. Among them is the amplification of the miR-17~92 gene, which encodes six distinct miRNAs, and the elevated expression of miR-17~92 miRNAs in cells carrying this gene amplification. We have generated a miR-17~92 transgene whose expression can be turned on conditionally by Cre recombinase in mice. Strikingly, the transgenic mice developed a lymphoproliferative and autoimmune disease, and died prematurely, when this transgene was turned on in both B and T lymphocytes using hCD2-iCre. Our preliminary studies showed that transgenic miR-17 ~ 92 expressions broke B cell tolerance in an anti-IgM macroself (5b-ms) superantigen transgenic model. We hypothesize that transgenic miR-17~92 expression causes autoimmune diseases mainly by breaking B cell tolerance. We now propose studies to elucidate the cellular and molecular mechanisms underlying miR-17~92 mediated breaking of B cell tolerance and development of autoimmune diseases, and to illustrate how alterations in miRNA expression contribute to autoimmunity and how miRNA clusters carry out their functions. We will determine the contribution of transgenic miR-17~92 expression in B cells to the autoimmune disease (Aim 1), assess the impact of transgenic miR-17~92 expression on B cell tolerance checkpoints (Aim 2), dissect the functional contribution of individual miRNAs in the miR-17~92 cluster to the breaking of B cell tolerance (Aim 3), and identify target genes and molecular pathways whose deregulation leads to the autoimmune disease in miR-17~92 transgenic mice (Aim 4). We will combine genetic, proteomic, genomic, molecular, and bioinformatic approaches to achieve these goals.

描述（由申请人提供）：MicroRNAs （miRNAs）最近成为一类主要的反式因子，通过其3' utr调节蛋白质编码基因的表达，从而控制多种生物过程，包括细胞分化、增殖和凋亡。miRNAs与其靶基因的mRNA配对，通常的结果是通过翻译抑制、mRNA切割或促进mRNA衰变来下调蛋白质表达。已经在哺乳动物中发现了数百种mirna，其中许多是进化上保守的，这些分子中的一小部分在免疫系统中表现出高度特异性，受调节的表达模式。我们和其他研究小组的遗传学研究表明，mirna在淋巴细胞发育、免疫反应和淋巴瘤形成中起着关键作用。然而，我们对mirna在自身免疫性疾病中的作用知之甚少。在人类患者中发现了大量miRNA编码基因的遗传和表观遗传改变。其中包括miR-17~92基因的扩增，该基因编码六种不同的miRNAs，以及携带该基因扩增的细胞中miR-17~92 miRNAs的表达升高。我们已经在小鼠体内产生了一种miR-17~92转基因，它的表达可以被Cre重组酶有条件地开启。引人注目的是，当使用hCD2-iCre在B淋巴细胞和T淋巴细胞中开启这种转基因时，转基因小鼠患上了淋巴细胞增生性和自身免疫性疾病，并过早死亡。我们的初步研究表明，在抗igm巨自体（5b-ms）超抗原转基因模型中，转基因miR-17 ~ 92的表达打破了B细胞的耐受性。我们假设转基因miR-17~92表达主要通过破坏B细胞耐受性导致自身免疫性疾病。我们现在提出的研究旨在阐明miR-17~92介导的B细胞耐受性破坏和自身免疫性疾病发展的细胞和分子机制，并阐明miRNA表达的改变如何促进自身免疫以及miRNA簇如何发挥其功能。我们将确定B细胞中转基因miR-17~92表达对自身免疫性疾病的贡献（Aim 1），评估转基因miR-17~92表达对B细胞耐受检查点的影响（Aim 2），解剖miR-17~92簇中单个mirna对B细胞耐受破坏的功能贡献（Aim 3），并确定解除miR-17~92转基因小鼠自身免疫性疾病的靶基因和分子途径（Aim 4）。我们将结合遗传学，蛋白质组学，基因组学，分子和生物信息学方法来实现这些目标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of B-cell development and tolerance by different members of the miR-17∼92 family microRNAs.

DOI：
10.1038/ncomms12207
发表时间：
2016-08-02
期刊：
Nature communications
影响因子：
16.6
作者：
Lai M;Gonzalez-Martin A;Cooper AB;Oda H;Jin HY;Shepherd J;He L;Zhu J;Nemazee D;Xiao C
通讯作者：
Xiao C

An Integrated Polysome Profiling and Ribosome Profiling Method to Investigate In Vivo Translatome.