tRNA-derived stress-induced RNAs and translational control

tRNA 衍生的应激诱导 RNA 和翻译控制

基本信息

批准号：
10709543
负责人：
Pavel Ivanov
金额：
$ 35.8万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709543
关键词：
Address Affect Alanine-Specific tRNA Amyotrophic Lateral Sclerosis Anticodon Apoptosis Base Sequence Binding Biogenesis Biological Process Biology CRISPR/Cas technology Cell Survival Cell physiology Cells Cellular Stress Communities Complex Custom Cytoprotection Data Disease Elements Ensure Future Gene Expression Gene Expression Regulation Goals Health Human Human Pathology Immunity In Vitro Investigation Knowledge Laboratories Link Malignant Neoplasms Mediating Messenger RNA Methods Modeling Molecular Molecular Biology Mutation Neurodegenerative Disorders Nucleotides Nutrient Parkinson Disease Pathology Pathway interactions Patients Play Postdoctoral Fellow Process Production Property Protein Biosynthesis Proteins Proteomics RNA RNA Interference Reagent Regulator Genes Research Research Personnel Resources Ribonucleases Ribosomes Role Signal Transduction Source Stress Structure System Technology Testing Therapeutic Transcript Transfer RNA Translation Initiation Translational Regulation Translational Repression Translations Triplet Multiple Birth Untranslated RNA Work angiogenin biological adaptation to stress cohort human disease innovation insight mRNA Translation new therapeutic target novel novel therapeutics overexpression programs protein aminoacid sequence response ribosome profiling targeted treatment

项目摘要

Summary Transfer RNA (tRNA) is traditionally viewed as an adaptor molecule that helps ribosomes synthesize proteins by decoding nucleotide triplets linking mRNA sequence to amino acid sequence of protein. Recent findings demonstrate that tRNAs also serve as a major source of small non-coding RNAs, so called tRNA-derived fragments (tRFs). The emerging concept in molecular biology is that these tRFs perform regulatory functions, although relatively little is known about their precise roles in cell physiology. Work from our and other laboratories has shown that in response to a variety of abiotic stresses (e.g. oxidative or nutrient stress), the vertebrate-specific ribonuclease (RNase) angiogenin (ANG) is activated to target the anticodon loops of tRNAs to produce a specific subclass of tRFs, known as tRNA-derived stress-induced RNAs (tiRNAs). Since their discovery in 2009, tiRNAs have been found to play roles in stress adaptation, cell survival and apoptosis. One of the relatively well studied roles of selected subset of tiRNAs (derived from tRNAAla and tRNACys) is inhibition of translation initiation via interference with functions of the cap-binding complex eIF4F (Ivanov et al. Mol Cell 2011). This proposal will further investigate functions of novel, previously unexplored, tiRNAs in regulation of translation. Our preliminary data suggest that alternative mechanisms of translation modulation exist that are different from the mechanisms used by tiRNAAla/Cys. In Aim1, we will dissect the molecular mechanisms of tiRNA- mediated regulation of translation. Our preliminary data strongly support a model in which multiple non- overlapping mechanisms are used by specific tiRNAs to mediate both inhibition and stimulation of mRNA translation. In Aim 2, we will identify and characterize mRNA targets of tiRNAs by employing candidate and unbiased proteomic and ribosome profiling approaches. Our preliminary data suggest that specific tiRNAs target specific pool of mRNAs thus reprogramming cellular translation. Our proposal is highly innovative and will broadly impact RNA biology. Successful completion of the proposed studies will result in characterization of novel translational control mechanisms acting during stress. Our studies are also important from a therapeutic point of view because multiple pathophysiological conditions are linked to changes in tiRNA production. Mutations affecting the RNase activity of ANG are found in patients with the neurodegenerative diseases Amyotrophic Lateral Sclerosis and Parkinson’s disease. Also, ANG is over- expressed in multiple cancers and its expression correlates with misbalanced tiRNA production, indicating a necessity to understand the function of tiRNAs. Finally, this proposal will generate many resources for the entire RNA/tRNA community and we will ensure that these resources are available for future use.

概括转移 RNA (tRNA) 传统上被视为帮助核糖体合成的衔接分子通过解码连接 mRNA 序列和蛋白质氨基酸序列的核苷酸三联体来识别蛋白质。研究结果表明，tRNA 也是小非编码 RNA（所谓的 tRNA 衍生）的主要来源分子生物学中的新兴概念是这些 tRF 具有调节功能，尽管人们对它们在细胞生理学中的确切作用知之甚少。我们和其他实验室的工作表明，为了应对各种非生物胁迫（例如，氧化或营养应激），脊椎动物特异性核糖核酸酶（RNase）血管生成素（ANG）被激活以靶向 tRNA 的反密码子环产生特定的 tRF 亚类，称为 tRNA 衍生的应激诱导 RNA (tiRNA) 自从 2009 年被发现以来，人们发现 tiRNA 在应激适应、细胞中发挥作用。选定的 tiRNA 子集（源自 tRNAAla）的研究相对充分的作用之一。和 tRNACys）通过干扰帽结合复合物 eIF4F 的功能来抑制翻译起始（Ivanov 等人，Mol Cell 2011）。该提案将进一步研究以前未探索过的新型 tiRNA 在调节中的功能我们的初步数据表明存在替代的翻译调节机制：与tiRNAAla/Cys使用的机制不同，在Aim1中，我们将剖析tiRNA-的分子机制。我们的初步数据强烈支持一个模型，其中多个非特定 tiRNA 使用重叠机制来介导 mRNA 的抑制和刺激在目标 2 中，我们将通过使用候选和表征 tiRNA 的 mRNA 靶标。我们的初步数据表明，特定的 tiRNA 具有靶向性。特定的 mRNA 库，从而重新编程细胞翻译。我们的提案具有高度创新性，将广泛影响 RNA 生物学的成功完成。拟议的研究将导致在压力期间发挥作用的新型翻译控制机制的特征。从治疗的角度来看，我们的研究也很重要，因为多种病理生理条件与影响 ANG RNase 活性的 tiRNA 产生的变化有关。神经退行性疾病肌萎缩性脊髓侧索硬化症和帕金森病此外，ANG 过度。在多种癌症中表达，其表达与 tiRNA 产生失衡相关，表明最后，该提案将为整个组织提供许多资源。 RNA/tRNA 社区，我们将确保这些资源可供将来使用。