The role of host endogenous small RNAs in innate immunity

宿主内源小RNA在先天免疫中的作用

基本信息

批准号：
8499367
负责人：
Hailing Jin
金额：
$ 27.04万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
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：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499367
关键词：
Animal Model Anti-Bacterial Agents Arabidopsis Bacteria Bacterial Drug Resistance Bacterial Infections Biogenesis Biological Models Biological Process Code DNA Methylation Data Disease Resistance Epigenetic Process Eukaryota F Box Domain Functional RNA Gene Chips Gene Expression Gene Expression Regulation Gene Targeting Genes Genome Host Defense Immune System Diseases Immune response Immune system Immunity Infection Invertebrates Mammals Maps Mediating MicroRNAs Molecular Mouse-ear Cress Natural Immunity Organism Pathway interactions Plants Population Processed Genes Promoter Regions Proteins Pseudomonas syringae RNA Regulation Research Role Shotguns Small Interfering RNA Small RNA System Technology Tissues Transcript Translational Repression Vesicle Work bisulfite chromatin modification chromatin remodeling deep sequencing defense response mRNA Expression mRNA Transcript Degradation pathogen public health relevance response trafficking

项目摘要

DESCRIPTION (provided by applicant): Organisms, including mammals, invertebrates, and plants have evolved sophisticated and conserved innate immune responses to protect themselves from pathogen attacks. In these systems, host immune responses and disease resistance are achieved by modulation of a large array of genes, but how these processes are regulated is still largely unclear. Small RNAs are non-coding regulatory RNA molecules that control gene expression by mediating mRNA degradation, translational inhibition, or chromatin modification. Our work and those of others have demonstrated a role of host endogenous small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), in antibacterial innate immunity. We discovered that several pathogen-induced host endogenous siRNAs, including natural antisense transcripts-derived siRNAs (nat-siRNAs) and long siRNAs (lsiRNAs), facilitate host immune responses by posttranscriptionally silencing the negative regulators of plant immune systems. Epigenetic changes were also observed in bacteria-infected plants, however, the role of small RNA-guided DNA methylation and chromatin modification in plant immunity has not been explored. Using Arabidopsis as a model system and Illumina deep sequencing as a platform, we recently profiled the small RNA population after bacterium-challenge and identified diverse classes of endogenous small RNAs that are regulated by the infection of bacterial pathogens. We hypothesize that these pathogen-responsive small RNAs regulate the expression of genes involved in host immune responses by silencing regulators of host immunity transcriptionally or post-transcriptionally. We propose to investigate the regulation, biogenesis, and function of these pathogen-responsive small RNAs. Specifically, we will perform in depth characterization of several newly identified miRNAs, nat-siRNAs, lsiRNAs, and clustered hc-siRNAs that are particularly regulated by various strains of the bacterium Pseudomonas syringae. Predicted target genes of these small RNAs will be validated and subjected to functional analysis. These targets are likely to be components involved in plant immune response pathways. We will also characterize the hc-siRNAs that directed DNA methylation in response to bacterial infection. We will generate a whole-genome DNA-methylation map before and after bacterial infection, and correlate the siRNAs, DNA methylation, and pathogen-responsive gene expression. The proposed research will significantly advance our understanding of the mechanisms and functions of small RNAs involved in host innate immunity. PUBLIC HEALTH RELEVANCE: Multicellular eukaryotes, including mammals, invertebrates, and plants have evolved sophisticated and conserved innate immune responses to protect themselves from pathogen attack. The proposed research will significantly advance our understanding of the mechanisms and function of small RNA-mediated gene regulation in innate immunity using the model organism Arabidopsis thaliana.

描述（由申请人提供）：包括哺乳动物，无脊椎动物和植物在内的生物已经进化出复杂和保守的先天免疫反应，以保护自己免受病原体攻击。在这些系统中，通过调节大量基因来实现宿主免疫反应和抗病性，但是如何调节这些过程仍然不清楚。小RNA是非编码调节RNA分子，通过介导mRNA降解，翻译抑制或染色质修饰来控制基因表达。我们的工作以及其他的工作表现出了宿主内源性小RNA的作用，包括microRNA（miRNA）和小型干扰RNA（siRNA）在抗菌先天免疫中的作用。我们发现，几种病原体诱导的宿主内源性siRNA，包括自然反义转录物衍生的siRNA（NAT-SIRNAS）和长siRNA和长siRNA（LSIRNAS），通过在转录后沉默植物免疫系统的负调节剂来促进宿主免疫反应。在细菌感染的植物中也观察到了表观遗传变化，但是，尚未探索小RNA引导的DNA甲基化和染色质修饰在植物免疫中的作用。我们使用拟南芥作为模型系统和Illumina Deep测序作为平台，最近我们介绍了细菌 - 挑战后的RNA群，并确定了受细菌病原体感染调节的各种内源性小RNA。我们假设这些病原体响应的小RNA通过沉默的转录或转录后宿主免疫的调节剂来调节与宿主免疫反应有关的基因的表达。我们建议研究这些病原体反应性小RNA的调节，生物发生和功能。具体而言，我们将对几种新鉴定的miRNA，NAT-SIRNA，LSIRNA和聚类的HC-SIRNA进行深入表征，这些miRNA，NAT-SIRNA，LSIRNA和聚类的HC-SIRNA特别受到丁香细菌菌株的各种菌株的调节。这些小RNA的预测靶基因将得到验证并进行功能分析。这些靶标可能是参与植物免疫反应途径的组成部分。我们还将表征针对细菌感染的HC-SIRNA，该HC-siRNA指示DNA甲基化。我们将在细菌感染前后产生全基因组DNA-甲基化图，并将siRNA，DNA甲基化和病原体反应性基因表达相关。拟议的研究将大大提高我们对宿主先天免疫涉及的小型RNA的机制和功能的理解。公共卫生相关性：包括哺乳动物，无脊椎动物和植物在内的多细胞真核生物已经进化出复杂和保守的先天免疫反应，以保护自己免受病原体攻击。拟议的研究将大大提高我们对使用模型有机体拟南芥在先天免疫中小RNA介导的基因调节的机制和功能的理解。