Project description DEENESFRITPL Novel insights into the in vivo role of an enigmatic stress response The ribotoxic stress response (RSR), conserved between prokaryotes and eukaryotes, was first described more than two decades ago. Even at that early stage of research, the RSR was shown to be triggered in mammalian cells by exposure to ultraviolet radiation. Since then, this cytotoxic interference with the function of ribosomal RNA has also been linked to infection with Shiga toxin-producing bacteria and with side effects from some forms of chemotherapy. However, despite decades of research, the relevance of the RSR signalling pathway to the normal functioning of mammalian cells is unknown. The EU-funded PHYRIST project plans to shed light on this highly conserved yet enigmatic stress response and its role in vivo. Insight should point the way to novel therapeutic targets for skin cancer, bacterial infections and ageing processes, among many others. Show the project objective Hide the project objective Objective The ribotoxic stress response (RSR) surveys the structural and functional integrity of ribosomes and is triggered by diverse groups of ribotoxins (e.g. ricin), UV irradiation and some chemotherapeutics. When presented with impaired ribosomes, the proximal MAPKKK ZAK activates MAP kinases p38 and JNK to initiate a powerful inflammatory response. This signalling contributes to the detrimental reactions to ribotoxins and fatal side effects of cancer therapy. However, despite decades of research into the RSR, the physiological relevance of the underlying pathway in whole organisms is unknown. I hypothesize that the RSR constitutes a general translation quality control pathway and hence I aim to uncover the physiological and pathological implications of RSR impairment in mice and nematodes.In one line of investigation, I will elucidate the connections between UV radiation and RSR-mediated p38 activation. I hypothesize that this signalling pathway is critical for sunlight-induced skin inflammation and development of skin cancers of different cellular origins. Rewardingly, we found that cells from our ZAK knockout (KO) mice are refractory to UV-induced p38 activation, which is a significant contributor to skin cancer development. My team has also observed deregulation of protein translation in RSR-deficient human and mouse cells, and a reduced lifespan of ZAK KO nematodes. Thus encouraged, I will determine the impact of the RSR pathway on cancer development and aging processes in mice, and I will unravel the molecular connections between defective ribosomes, RSR activation and regulation of translation. Finally, I am in a unique position to evaluate the RSR as a putative drug target and I will investigate the potential of ZAK inhibition to treat or prevent skin cancer, and to remedy inflammation arising from infection with ribotoxin-producing bacteria. In sum, PHYRIST will yield the first detailed insight into the in vivo relevance of the ribotoxic stress response. Fields of science medical and health sciencesclinical medicineoncologyskin cancernatural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-COG - ERC Consolidator Grant Call for proposal ERC-2019-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Coordinator KOBENHAVNS UNIVERSITET Net EU contribution € 1 997 678,00 Address Norregade 10 1165 Kobenhavn Denmark See on map Region Danmark Hovedstaden Byen København 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 Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all KOBENHAVNS UNIVERSITET Denmark Net EU contribution € 1 997 678,00 Address Norregade 10 1165 Kobenhavn See on map Region Danmark Hovedstaden Byen København 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 Other funding € 0,00
