Objective Translation of the genetic code into functional proteins is a fundamental biological process essential for cell survival and function. tRNAs are critical in this process because they recognize the codons on the messenger RNA and bring the cognate amino acid to the nascent peptide. To become functional, tRNAs undergo a series of processing steps and chemical modifications. Recently, my host group discovered that cells lacking wobble uridine modifications in the tRNA anticodon display translational slow down, a defect that triggers widespread protein aggregation in yeast and nematodes. These findings were the first to link tRNA metabolism to protein quality control and established tRNA metabolism as a novel layer in the regulation of protein homeostasis. However, the mechanisms underlying this phenomenon remain unknown.My goal is to elucidate how tRNA processing and modifications regulate protein quality control, by integrating genetic, biochemical, transcriptomic, translatomic and proteomic approaches.- First, I will identify tRNA biosynthesis genes that are critical for protein aggregation, by assessing global protein homeostasis in yeast cells lacking genes required for tRNA processing and modifications. - Second, I will characterize transcriptome-wide translation by ribosome profiling to determine whether protein aggregation phenotypes are accompanied by translational defect. This will reveal which tRNA processing and modifications are essential for optimal co-translational protein folding. - Finally, I will use yeast and nematode models of neurodegenerative diseases to test the functional importance of candidate steps of tRNA metabolism in disease-associated protein aggregation.My project will comprehensively address the link between tRNA metabolism and protein homeostasis. In particular, it will bridge RNA and protein quality control pathways and shed mechanistic insights into neurodegenerative diseases that originate from tRNA dysfunction. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein foldingnatural sciencesbiological sciencesgeneticsRNAnatural scienceschemical sciencesorganic chemistryaminesmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2016 - Individual Fellowships Call for proposal H2020-MSCA-IF-2016 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITAET BERN Net EU contribution € 112 951,40 Address HOCHSCHULSTRASSE 6 3012 Bern Switzerland See on map Region Schweiz/Suisse/Svizzera Espace Mittelland Bern / Berne Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 124 255,55 Participants (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Participation ended Germany Net EU contribution € 46 509,40 Address HOFGARTENSTRASSE 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 46 509,40