MicroRNA uridylation by Zcchc11 regulates pulmonary inflammation

Zcchc11 的 MicroRNA 尿苷化调节肺部炎症

基本信息

批准号：
8494686
负责人：
Matthew Robert Jones
金额：
$ 38.57万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2010-07-12 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494686
关键词：
Acute Lung Injury Address Adenine Bacteria Bacterial Pneumonia Binding Biological Bronchoalveolar Lavage Fluid C57BL/6 Mouse Cell Culture Techniques Cell Line Cell physiology Cells Data Diagnosis Elements Enzymes Equilibrium Escherichia coli Exhibits Functional RNA Gene Expression Gene Expression Regulation Goals Host Defense Hypoxemia Immune response In Vitro Infection Inflammation Inflammatory Insertional Mutagenesis Interleukin-6 Knowledge Lead Link Location Lung Lung Compliance Lung Inflammation Measures Mediating Messenger RNA MicroRNAs Modeling Modification Molecular Mus Mutate NF-kappa B Natural Immunity Neutrophil Infiltration Nucleotides Play Pneumonia Post-Transcriptional Regulation Prevention Process Production Proteins Public Health Pulmonary Edema RNA RNA library Recombinants Reporter Repression Research Role STAT3 gene Signal Transduction Site Small Interfering RNA Small RNA Streptococcus pneumoniae Structure System TNF gene Testing Time Tissues Transcript Translations Untranslated Regions Uridine Variant base burden of illness cytokine deep sequencing derepression design in vivo innovation insight lung injury mRNA Stability mutant new therapeutic target novel prevent protein expression public health relevance research study response tool uridylate

项目摘要

DESCRIPTION (provided by applicant): Lung infections represent a significant burden of disease worldwide and are a common cause of acute lung injury. The pulmonary immune response during bacterial pneumonia is a tightly regulated process that eliminates bacteria while preventing host tissue damage due to excessive inflammation. To orchestrate this delicate balance, host inflammatory cytokine production must be dynamically regulated by both transcriptional and post-transcriptional mechanisms of gene expression. MicroRNA (miRNA) is emerging as an important class of post-transcriptional regulators of multiple cellular processes including inflammation. Recent studies utilizing deep-sequencing of small RNAs have revealed a tremendous amount of sequence diversity of miRNA, however, the functional significance of these sequence variations is unknown. One enzyme known to contribute to miRNA diversity is Zcchc11, a uridyltransferase enzyme that adds uridines to the ends of specific miRNAs. In addition to miRNA editing, our preliminary data show that Zcchc11 regulates cytokine expression, thus suggesting that Zcchc11- mediated miRNA sequence modifications could play a significant role in the post- transcriptional control of cytokine production. We will pursue 3 aims to test the central hypothesis that Zcchc11 uridylates mature miRNAs during pneumonia to regulate cytokine expression and lung inflammation. 1) Test the hypothesis that cytokine- targeting miRNAs are uridylated by Zcchc11 during inflammatory conditions. 2) Test whether sequence elements within uridylated miRNAs and target mRNAs are required for Zcchc11-dependent cytokine expression. 3) Test the hypothesis that Zcchc11- regulated cytokines are essential determinants of the host defense and lung injury during pneumonia. The knowledge obtained from the studies performed in this proposal will be of biological significance for identifying novel molecular mechanisms of gene regulation, miRNA uridylation by Zcchc11, to alleviate the silencing of target mRNAs. Insights obtained from these studies may also be medically significant in that a better understanding of how miRNA editing impacts the host response during pneumonia may lead to new avenues for diagnosis and prevention.

描述（由申请人提供）：肺部感染代表了全球疾病的重大负担，是急性肺损伤的常见原因。细菌性肺炎期间的肺免疫反应是一个严格调节的过程，可消除细菌，同时防止由于过度炎症而导致宿主组织损伤。为了策划这种微妙的平衡，宿主的炎症细胞因子的产生必须通过基因表达的转录和转录后的转录机制来动态调节。 MicroRNA（miRNA）正在成为重要的多个细胞过程的转录后调节剂，包括炎症。使用小型RNA进行深入序列的最新研究表明，miRNA的序列多样性巨大，但是，这些序列变化的功能意义尚不清楚。 ZCCHC11是一种已知有助于miRNA多样性的酶，这是一种尿苷转移酶，可在特定miRNA的末端添加尿苷。除miRNA编辑外，我们的初步数据表明，ZCCHC11调节细胞因子的表达，因此表明ZCCHC11-介导的miRNA序列修饰可能在细胞因子产生的转录后控制中起重要作用。我们将追求3个旨在检验ZCCHC11尿中的中心假设，即肺炎期间成熟的miRNA，以调节细胞因子表达和肺部炎症。 1）检验以下假设：靶向miRNA的细胞因子在炎症条件下被ZCCHC11尿液化。 2）测试是否需要尿苷的miRNA和靶mRNA中的序列元件才能依赖于ZCCHC11的细胞因子表达。 3）检验ZCCHC11调节的细胞因子是肺炎期间宿主防御和肺损伤的基本决定因素的假设。从该提案中进行的研究获得的知识将具有生物学意义，可用于鉴定基因调节的新分子机制，通过ZCCHC11减轻靶mRNA的沉默。从这些研究获得的见解也可能具有医学意义，因为更好地了解miRNA编辑如何影响肺炎期间宿主反应的方式可能会导致新的诊断和预防途径。