Advancing Transfer RNA Discovery, Research and Resources

推进转移 RNA 发现、研究和资源

• 批准号: 8277147
• 负责人: Todd Michael Lowe
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277147
• 关键词: Alzheimer' s Disease; Antibiotics; Bacteria; Biochemistry; Biological; Biological Assay; Biological Testing; Biomedical Research; Blindness; Cardiomyopathies; Cell division; Cells; Collection; Communities; Complex; DNA; Data; Databases; Detection; Diabetes Mellitus; Enzymes; Eukaryota; Genes; Genome; Genomics; Grant; Human; Individual; Lead; Life; Link; Maps; Measures; Methods; Mitochondria; Modeling; Modification; Molecular; Mutation; Myoclonic Epilepsies; Parkinson Disease; Phylogenetic Analysis; Process; Prokaryotic Cells; Proteins; Pseudogenes; RNA; Recurrence; Regulation; Research; Research Personnel; Resources; Role; Sampling; Structure; Technology; Transfer RNA; Variant; Work; Yeasts; base; cancer therapy; cell growth regulation; comparative genomics; design; hearing impairment; human disease; improved; insight; novel; pathogen; research study; tool; tumorigenesis

DESCRIPTION (provided by applicant): The broad objective of this project is to better understand tRNA function, regulation, and the dynamic contributions of individual tRNAs within the cell. Given the rapidly growing collection of genomic data and high throughput RNA detection methods, there are new opportunities to advance tRNA research if known limitations in our computational and molecular detection methods are overcome. Thus, the aims of this grant are: (1) To expand and improve the technology of computational tRNA detection, (2) To provide a comprehensive database and advanced analysis tools enabling new biological insights and experimentation by the tRNA research community, (3) To measure the complex dynamics of tRNA abundance to understand the regulation and cellular roles of individual tRNA gene loci (4) To identify and test the biological contribution of atypical but evolutionarily recurrent tRNAs which challenge our conventional understanding of tRNA sequence and structure To achieve these aims, we will develop improved tRNA detection methods based on a greatly expanded sampling of tRNA diversity, with new, more specialized probabilistic search models. With major improvements in the design, content, and function of the Genomic tRNA Database, we will provide the most complete and up-to-date collection of tRNAs and on-line tools for tRNA researchers. To link expression data to specific tRNA loci, we will collect a wide phylogenetic sampling of tRNA-seq data, utilizing specialized mapping and normalization methods. To better understand what distinguishes a functional tRNA from a pseudogene, we will use comparative genomics and traditional biochemistry to assay function of a diverse set of natural tRNA variants in yeast. These tools, data resources, and studies will enable and accelerate biomedical research in the tRNA community. tRNA researches study a wide variety of human diseases that can be caused by mutations in mitochondrial tRNAs including diabetes, blindness, myoclonic epilepsy, cardiomyopathy, Alzheimer's Disease, Parkinson's Disease, and neurosensory hearing loss. Because increased tRNA abundance is required for rapid cell division in tumorigenesis, identification of disregulated tRNA loci could lead to new targets for cancer therapies. Finally, processing, editing, and modification of tRNAs differ in many ways between bacteria and eukaryotes - closer study of these phylogenetic differences could offer opportunities to develop novel antibiotics based on pathogen-specific tRNA processing enzymes. PUBLIC HEALTH RELEVANCE: This project will advance research of transfer RNA genes, which are universal to all life and central to the accurate transfer of information from DNA to proteins. Mutations in tRNA genes or changes in their regulation are known to cause a broad range of human disease. This work will provide the tools and information to researchers to enable them to study tRNAs in human cells and all other species that have decoded genomes.

描述（由申请人提供）：该项目的总体目标是更好地了解 tRNA 功能、调节以及细胞内各个 tRNA 的动态贡献。鉴于基因组数据收集和高通量 RNA 检测方法的快速增长，如果我们的计算和分子检测方法中已知的局限性得到克服，就会有新的机会推进 tRNA 研究。因此，这笔赠款的目的是：(1) 扩展和改进计​​算 tRNA 检测技术，(2) 提供全面的数据库和先进的分析工具，使 tRNA 研究界能够获得新的生物学见解和实验，(3) 测量 tRNA 丰度的复杂动态，以了解单个 tRNA 基因位点的调节和细胞作用 (4) 识别和测试非典型但进化上重复的生物贡献 tRNA 挑战了我们对 tRNA 序列和结构的传统理解 为了实现这些目标，我们将基于大大扩展的 tRNA 多样性采样，以及新的、更专业的概率搜索模型，开发改进的 tRNA 检测方法。随着基因组 tRNA 数据库的设计、内容和功能的重大改进，我们将为 tRNA 研究人员提供最完整、最新的 tRNA 集合和在线工具。为了将表达数据与特定 tRNA 位点联系起来，我们将利用专门的作图和标准化方法收集 tRNA-seq 数据的广泛系统发育样本。为了更好地理解功能性 tRNA 与假基因的区别，我们将使用比较基因组学和传统生物化学来分析酵母中多种天然 tRNA 变体的功能。 这些工具、数据资源和研究将促进并加速 tRNA 领域的生物医学研究。 tRNA 研究研究由线粒体 tRNA 突变引起的多种人类疾病，包括糖尿病、失明、肌阵挛性癫痫、心肌病、阿尔茨海默病、帕金森病和神经感觉性听力损失。由于肿瘤发生过程中的快速细胞分裂需要增加 tRNA 丰度，因此识别失调的 tRNA 位点可能会为癌症治疗带来新的靶点。最后，细菌和真核生物之间 tRNA 的加工、编辑和修饰在许多方面存在差异 - 对这些系统发育差异的更深入研究可以为开发基于病原体特异性 tRNA 加工酶的新型抗生素提供机会。 公共健康相关性：该项目将推进转移 RNA 基因的研究，这些基因对所有生命来说都是通用的，对于信息从 DNA 到蛋白质的准确转移至关重要。已知 tRNA 基因突变或其调控变化会导致多种人类疾病。这项工作将为研究人员提供工具和信息，使他们能够研究人类细胞和所有其他已解码基因组的物种中的 tRNA。