Role of proinflammatory tRNA-derived RNAs in asthma

促炎性 tRNA 衍生的 RNA 在哮喘中的作用

• 批准号: 9298140
• 负责人: Yohei Kirino
• 金额: $ 23.4万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298140
• 关键词: Allergic; Allergic inflammation; Amino Acids; Anticodon; Asthma; Biogenesis; Biological Markers; Breathing; Bronchoconstriction; Cell Cycle Regulation; Cell physiology; Cells; Chronic; Data; Development; Disease; Effector Cell; Etiology; Extrinsic asthma; Gene Expression; Gene Expression Regulation; Generations; Genetic Transcription; Goals; Gonadal Steroid Hormones; Growth; Growth Factor; Hormones; Human; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Interleukin-13; Investigation; Knowledge; Lung; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Mucous body substance; Mus; Muscle Cells; Nerve Degeneration; Pathogenesis; Pathway interactions; Periodicity; Phenotype; Play; Positioning Attribute; Process; Production; Pyroglyphidae; RNA; Regulation; Regulator Genes; Research; Role; Small Interfering RNA; Small RNA; Source; Stress; Subgroup; TNF gene; Therapeutic; Time; Tissue Sample; Transcriptional Regulation; Transfer RNA; Translations; Untranslated RNA; airway remodeling; asthmatic; asthmatic airway; autocrine; cell growth; chemokine; cytokine; human disease; inflammatory lung disease; inorganic phosphate; insight; mouse model; novel; novel marker; novel therapeutics; oncoprotein p21; paracrine; protein function; respiratory smooth muscle; tool; transcriptome; transcriptome sequencing

Project Summary and Abstract Asthma is a chronic inflammatory disease characterized by inflammation, mucus production, airway remodeling, and hyper-responsiveness resulting in severe bronchoconstriction. These processes involve interplay among resident airway cells and infiltrated inflammatory cells. Allergic inflammatory mediators such as cytokines, chemokines, and growth factors act on resident airway cells including airway smooth muscle (ASM) resulting in structural and functional changes. However, knowledge gaps remain in our understanding of the molecular factors and mechanisms by which inflammatory mediators modulate ASM phenotype. Inflammatory mediators change gene expression and contribute to the pathogenesis of asthma. Transcriptional regulation of gene expression in resident airway cells has been studied extensively. However, protein function in a target cell can be regulated at multiple levels starting from transcription followed by post-transcription, translation and post-translation steps. In this context, small non-coding RNAs (ncRNAs) including the ones derived from transfer RNA (tRNA) have evolved as one of the key regulators of gene expression post-transcriptionally. We propose that tRNA halves, a major subgroup of tRNA-derived ncRNAs, play important roles in asthma pathobiology and can be targeted as asthma therapy. In preliminary studies, we found that mouse lung expresses specific tRNA half species whose levels are significantly upregulated during allergic inflammation caused by inhaled challenge of house dust mite (HDM). Furthermore, human ASM cells express tRNA halves and their expressions are promoted by treatments with pro-inflammatory and Th2 cytokines, tumor necrosis factor alpha (TNF) and interleukin 13 (IL-13). These results allow us to define the tRNA halves as a novel class of cytokine-dependent tRNA halves, termed proinflammatory tRNA-derived RNAs (pit-RNAs). Importantly, siRNA-directed depletion of pit-RNAs significantly impaired the proliferation of ASM cells, suggesting that pit-RNAs are not just accumulated as degradation by-products of tRNAs but are expressed as functional RNAs promoting ASM cell growth. These results have led us to hypothesize that inflammatory mediators accumulate pit-RNAs in ASM cells, which enhance ASM growth in the molecular pathogenesis of asthma. We propose to comprehensively identify pit-RNA expression profiles (Aim 1) and investigate molecular mechanisms of the pit-RNA-mediated modulation of ASM cell function (Aim 2), which will reveal a novel tRNA-engaged small RNA pathway in the pathogenesis of asthma and support the exploration of biomarkers and efficacious therapeutic applications targeting tRNA halves. .

项目摘要和摘要 哮喘是一种以感染，粘液产生，气道为特征的慢性炎症性疾病 重塑和过度反应性，导致严重的支气管收缩。这些过程 涉及居民气道细胞和浸润的炎症细胞之间的相互作用。过敏性炎症 细胞因子，趋化因子和生长因子等介体对居民气道细胞作用，包括 气道平滑肌（ASM）导致结构和功能变化。但是，知识差距 保持我们对炎症介质的分子因素和机制的理解 调节ASM表型。炎症介质改变基因表达，并有助于 哮喘的发病机理。居民气道细胞中基因表达的转录调节一直是 广泛研究。但是，靶细胞中的蛋白质功能可以在多个级别开始调节 从转录，然后是转录后，翻译和翻译后步骤。在这种情况下， 小型非编码RNA（NCRNA），包括转移RNA（tRNA）的无编码RNA（ncRNA）已进化 作为转录后基因表达的关键调节剂之一。 我们提出，tRNA一半是tRNA衍生的ncRNA的主要亚组，在 哮喘病理生物学，可以靶向哮喘治疗。在初步研究中，我们发现 小鼠肺表达特定的tRNA半物种，其水平在 由房屋尘螨（HDM）吸入挑战引起的过敏性炎症。此外，人类ASM 细胞表达tRNA的一半及其表达是通过促炎和 Th2细胞因子，肿瘤坏死因子α（TNF）和白介素13（IL-13）。这些结果使我们能够 将tRNA一半定义为一类新型的细胞因子依赖性tRNA一半，称为促炎 tRNA衍生的RNA（PIT-RNA）。重要的是，PIT-RNA的siRNA定向耗竭 ASM细胞的增殖受损，表明PIT-RNA不仅累积为 TRNA的降解副产品，但表示为促进ASM细胞生长的功能性RNA。 这些结果使我们假设炎症介体在ASM中积累了PIT-RNA 细胞，可增强哮喘分子发病机理中ASM的生长。我们建议 全面识别PIT-RNA表达谱（AIM 1）并研究的分子机制 ASM细胞功能的PIT-RNA介导的调制（AIM 2），它将揭示新的tRNA参与 哮喘发病机理中的小RNA途径并支持生物标志物和 靶向tRNA的一半的有效治疗应用。 。