Role of Toll-like receptor-induced short non-coding RNAs in innate immune response

Toll样受体诱导的短非编码RNA在先天免疫反应中的作用

• 批准号: 10312129
• 负责人: Yohei Kirino
• 金额: $ 19.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312129
• 关键词: Amino Acids; Anticodon; Biogenesis; Biological; Biological Markers; Bovine Tuberculosis; Cell surface; Communicable Diseases; Data; Disease; Elements; Endosomes; Foundations; Future; Generations; Genetic Transcription; Goals; Gonadal Steroid Hormones; Human; Immune; Immune response; Infection; Innate Immune Response; Innate Immune System; Investigation; Knock-out; Ligands; Link; Lipopolysaccharides; Lysosomes; Malignant Neoplasms; Mammalian Cell; Membrane; Messenger RNA; Methods; Microbe; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Pathway interactions; Pattern; Pattern Recognition; Pattern recognition receptor; Peptidoglycan; Periodicity; Play; Positioning Attribute; Prevention; Process; Production; RNA; Receptor Activation; Regulation; Research; Role; Signal Pathway; Signal Transduction Pathway; Source; Stress; Subgroup; Surface; Symptoms; System; TLR7 gene; Therapeutic; Toll-Like Receptor Pathway; Toll-like receptors; Transcription Factor AP-1; Transcriptional Activation; Transcriptional Regulation; Transfection; Transfer RNA; Untranslated RNA; Up-Regulation; angiogenin; cell type; chemokine; cytokine; experimental study; extracellular; human disease; immune activation; inorganic phosphate; insight; macrophage; monocyte; novel; pathogen; pathogenic microbe; response; therapeutic target; tool; transcription factor; transcriptome sequencing; tumorigenesis

Project Summary and Abstract Infection of microbes causes a wide range of symptoms and diseases. Sustained efforts to understand the mechanism of cellular defense systems against microbe infections are essential to develop effective prevention methods and therapeutic applications. The innate immune system deploys various pattern-recognition receptors, including Toll-like receptors (TLRs), to recognize the invasion of microbes and initiate protective responses. TLRs are expressed at the cell surface or intracellular compartments (e.g., endosome and lysosome) in various cell types, such as macrophages, and recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and peptidoglycan (PGN). The PAMP recognition initiates signal transduction pathways that culminate in the activation of transcription factors such as NF-κB, resulting in production of cytokines and chemokines to protect the host. Following transcriptional regulation, the downstream of TLR pathways involves regulation at multiple levels including post-transcription steps. In this context, short non- coding RNAs (ncRNAs) including those derived from transfer RNAs (tRNAs) have evolved as key post- transcriptional regulators. tRNA halves constitute a major subgroup of tRNA-derived ncRNAs and have been shown to be expressed as functional RNAs associated with various biological pathways and linked to human diseases such as neurodegenerative diseases and cancers. The goal of our proposed studies is to elucidate the expression profile and molecular function of tRNA half molecules whose accumulation is involved in the innate immune response. We recently found that the infection of Mycobacterium bovis BCG upregulates the expression of tRNA halves in human monocyte-derived macrophages (HMDMs). Furthermore, the expression of tRNA halves in HMDMs is upregulated by the activation of surface membrane TLRs, allowing us to define the tRNA halves as a novel class of TLR pathway-dependent tRNA halves. Importantly, tRNA halves are abundantly accumulated not only in TLR pathway-activated HMDMs but also in their extracellular vehicles (EVs) and have functional significance in activation of endosomal TLR pathway, suggesting that those tRNA halves are expressed as functional molecules promoting immune response. These results have led us to hypothesize that tRNA halves can be integral elements in the innate immune response. We propose to comprehensively identify the expression profiles of TLR pathway-induced tRNA halves in HMDMs and their EVs (Aim 1), to investigate the biogenesis mechanism how the production of tRNA haves are induced by TLR pathways (Aim 2), and to elucidate the molecular function of tRNA halves in endosomal TLR activation (Aim 3). Our study will reveal a novel tRNA-engaged ncRNA pathway in the innate immune response and may support the future exploration of biomarkers and efficacious therapeutic applications targeting tRNA half molecules upon microbe infection.

项目摘要和摘要 微生物的感染会引起广泛的症状和疾病。持续努力了解 细胞防御系统针对微生物感染的机制对于发展有效的预防至关重要 方法和治疗应用。先天免疫系统部署了各种模式识别受体， 包括Toll样受体（TLR），以识别微生物的侵袭并启动保护反应。 TLR在细胞表面或细胞内室（例如内体和溶酶体）中表达。 细胞类型，例如巨噬细胞，并识别病原体相关的分子模式（PAMP），例如 脂多糖（LPS）和Pepperidoglycan（PGN）。 PAMP识别启动信号转导 最终导致转录因子（例如NF-κB）的途径，导致产生 细胞因子和趋化因子保护宿主。在转录调节后，TLR的下游 途径涉及多个级别的调节，包括转录后步骤。在这种情况下，简短的非 - 编码RNA（NCRNA），包括从转移RNA（TRNA）衍生的RNA，已演变为关键后 tRNA一半构成了tRNA衍生的NCRNA的主要子组，并且已经 被证明表示为与各种生物学途径相关的功能性RNA，并与人类相关 神经退行性疾病和癌症等疾病。我们提出的研究的目的是阐明 tRNA半分子的表达谱和分子功能，其积累与先天有关 免疫反应。我们最近发现，牛分枝杆菌BCG的感染上调了表达 人类单核细胞衍生的巨噬细胞（HMDMS）中的tRNA一半。此外，tRNA的表达 HMDMS中的一半是通过表面膜TLR的激活来更新的，从而使我们能够定义tRNA 一半是一类新型TLR途径依赖性tRNA的一半。重要的是，tRNA半是绝对的 不仅在TLR途径激活的HMDM中积累 内体TLR途径激活中的功能显着性，表明那些tRNA的一半是 表示为促进免疫激素的功能分子。这些结果使我们假设 tRNA半半可以是先天免疫反应中不可或缺的元素。我们建议全面识别 TLR途径诱导的HMDMS及其EV中的TRNA一半的表达曲线（AIM 1），以研究 生物发生机制如何通过TLR途径诱导tRNA的产生（AIM 2），而对 阐明内体TLR激活中tRNA一半的分子功能（AIM 3）。我们的研究将揭示 新颖的tRNA引入的NCRNA途径在先天免疫反应中，并可能支持未来的探索 生物标志物和有效的靶向tRNA半分子在微生物感染时的治疗应用。