Research
The focus of the Orellana Lab is to study and research the causes and effects of tRNA dysregulation in human disease (Directions 1 and 2), and to use this knowledge to develop tRNA-based therapeutics and diagnosis (Direction 3).
The lab applies a diverse set of state-of-the-art molecular, cellular, and in vivo approaches, including RNA and protein biochemistry, RNA-sequencing, ribosome profiling, RNA modification profiling using RNA-Mass Spectrometry and sequencing based technologies, and CRISPR- and chemical-screening to provide mechanistic insights into the underlying causes of the dysregulation of tRNA function.
Direction one.
To understand mechanisms of tRNA dysregulation.
tRNA dysregulation either by changes in abundance and/or function are the underlying causes of several human malignancies. However, for many years the importance and contribution of tRNAs to human disease has been overlooked and in fact, tRNA sequencing data is often treated as contamination and discarded from RNA sequencing analyses. In the last few years, more attention has been given to tRNAs, but a comprehensive analysis of tRNA dysregulation is still lacking.
Direction two.
Define the mechanisms that control tRNA quality in mammals.
RNA quality control is a critical aspect of RNA life and function. Its main enforcers are ribonuclease enzymes that eliminate aberrant or unnecessary RNAs, which would otherwise cause diseases. This is also true for tRNAs, as illustrated by the discovery of the rapid tRNA decay pathway (RTD) in yeast, which removes defective hypomodified tRNAs. Although a similar mechanism to the RTD pathway in yeast exists in mammals, the specific enzymes responsible for tRNA surveillance remain unknown.
Direction three.
To develop tRNA based therapeutics and to understand the functional roles of individual tRNAs.
The central premise of this research angle is that tRNAs are viable drug targets because they play a vital role in defining the onco-proteome through widespread shifts in translation. Targeting tRNAs in cancer is thus far unexplored because we have not been able to separate an oncogenic target from the complex pool of ubiquitously expressed and functioning cellular tRNAs.