Advancing Transfer RNA Discovery, Research and Resources

描述（由申请人提供）：这个项目的总体目标是更好地了解细胞内单个tRNA的功能、调控和动态贡献。鉴于基因组数据和高通量RNA检测方法的快速增长，如果我们的计算和分子检测方法的已知局限性被克服，将有新的机会推进tRNA研究。因此，这项赠款的目的是：(1)扩展和改进计算tRNA检测技术；(2)为tRNA研究界提供一个全面的数据库和先进的分析工具，使新的生物学见解和实验成为可能；(3)为了测量tRNA丰度的复杂动态，以了解单个tRNA基因位点的调控和细胞作用(4)为了识别和测试非典型但进化上复发的tRNA的生物学贡献，这些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，我们将开发改进的tRNA检测方法，基于大大扩展的tRNA多样性采样，使用新的，更专业的概率搜索模型。随着基因组tRNA数据库在设计、内容和功能上的重大改进，我们将为tRNA研究人员提供最完整和最新的tRNA集合和在线工具。为了将表达数据与特定的tRNA位点联系起来，我们将利用专门的制图和归一化方法，收集广泛的tRNA-seq数据的系统发育样本。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社区的生物医学研究。tRNA研究研究了多种可能由线粒体tRNA突变引起的人类疾病，包括糖尿病、失明、肌阵挛性癫痫、心肌病、阿尔茨海默病、帕金森病和神经性听力损失。由于肿瘤发生过程中细胞快速分裂需要增加tRNA丰度，因此鉴定失调的tRNA位点可能为癌症治疗带来新的靶点。最后，细菌和真核生物对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能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。

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.