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.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
1R01HG006753-01
Application #
8277147
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Pazin, Michael J
Project Start
2012-07-16
Project End
2015-04-30
Budget Start
2012-07-16
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$500,000
Indirect Cost
$162,588
Name
University of California Santa Cruz
Department
None
Type
Schools of Engineering
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064