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. .

项目概要和摘要 哮喘是一种慢性炎症性疾病，其特征是炎症、粘液产生、气道 重塑和高反应性导致严重的支气管收缩。这些过程 涉及气道驻留细胞和浸润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质作用于气道常驻细胞，包括 气道平滑肌（ASM）导致结构和功能变化。然而，知识差距 仍然是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 哮喘的发病机制。常驻气道细胞基因表达的转录调控 广泛研究。然而，靶细胞中的蛋白质功能可以在多个水平上进行调节 从转录开始，然后是转录后、翻译和翻译后步骤。在此背景下， 小非编码 RNA (ncRNA) 包括源自转移 RNA (tRNA) 的小非编码 RNA (ncRNA) 已经进化 作为转录后基因表达的关键调节因子之一。 我们认为 tRNA 半体是 tRNA 衍生的 ncRNA 的一个主要亚类，在 哮喘病理学并可作为哮喘治疗的目标。在初步研究中，我们发现 小鼠肺表达特定的 tRNA 半种，其水平在 吸入屋尘螨 (HDM) 引起的过敏性炎症。此外，人类 ASM 细胞表达 tRNA 一半，并且促炎和促炎治疗可促进其表达 Th2 细胞因子、肿瘤坏死因子 α (TNFα) 和白细胞介素 13 (IL-13)。这些结果使我们能够 将 tRNA 半部定义为一类新型的细胞因子依赖性 tRNA 半部，称为促炎性 tRNA 衍生的 RNA (pit-RNA)。重要的是，siRNA 引导的pit-RNA 的消耗显着 损害 ASM 细胞的增殖，表明pit-RNA 不仅仅作为 tRNA 的降解副产物，但表达为促进 ASM 细胞生长的功能性 RNA。 这些结果使我们推测炎症介质在 ASM 中积累pit-RNA 细胞，在哮喘的分子发病机制中增强 ASM 的生长。我们建议 全面鉴定pit-RNA表达谱（目标1）并研究其分子机制 pit-RNA 介导的 ASM 细胞功能调节（目标 2），这将揭示一种新的 tRNA 参与 小RNA通路在哮喘发病机制中的作用并支持生物标志物的探索和 针对 tRNA 半部的有效治疗应用。 。