We use chemical tools to understand and manipulate how RNA maturation and decoding are spatially regulated in the etiology of human disease.
In all living beings, information is stored as DNA, transcribed into RNA, and translated into proteins – disruption of this process at any step has severe consequences. We combine small molecule compounds, protein and genome engineering, and cell biology to understand how the localization of RNA and protein in the cell can impact inflammation as well as neurological and developmental disorders.
The long-term goal of the lab is to translate this understanding into potential avenues for therapeutics but also to follow our curiosity and study new and unexpected functions of biomolecules.
Aminoacyl-tRNA synthetases
Aminoacyl-tRNA synthetases are an ancient protein class which recognize both an RNA adapter (tRNAs, see below) and the corresponding amino acid to produce the building blocks for protein synthesis. In addition, aminoacyl-tRNA synthetases fulfill unexpected functions in the regulation of mRNA translation and other cellular processes.
Mutations in aminoacyl-tRNA synthetases can cause neurological disorders and we hope to contribute to the understanding of these diseases. To this end, we will explore where in mammalian cells aminoacylation reactions take place and how that might affect cellular processes.
tRNAs
Transfer-RNAs (tRNAs) are adapters that connect the nucleic acid and the protein world. Recently, regulatory functions of tRNAs have been discovered and we have gained a new appreciation as to how comparatively small differences in tRNA levels can be detrimental for cellular processes.
We have found that during inflammation, tRNA levels are reduced. We aim to use metabolic labeling to tag and track tRNAs throughout various processing steps and cellular export. Our goal is to broaden our understanding of the different processes tRNAs and tRNA-derived fragments are involved in, specifically in the context of inflammation and immune cell activation.
Nuclear organization
The cell nucleus is divided into compartments that are structured through distinct properties of nuclear proteins. This enables mammalian cells to regulate their gene expression and mRNA processing.
Mutations in a specific protein can cause developmental disorders. We aim to investigate these mutations by introducing them into model cell lines to set up a screening platform to interrogate small molecular libraries with the goal of identifying lead compounds. These could potentially be used to correct the mutations in these proteins.