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PHYRIST SIGNED

Physiological roles of the Ribotoxic Stress Response

Total Cost €

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EC-Contrib. €

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Partnership

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 PHYRIST project word cloud

Explore the words cloud of the PHYRIST project. It provides you a very rough idea of what is the project "PHYRIST" about.

detrimental    hence    vivo    chemotherapeutics    found    prevent    zak    signalling    unravel    functional    inflammation    ribotoxins    structural    sunlight    regulation    constitutes    despite    stress    position    map    mediated    uncover    sum    first    reactions    rewardingly    bacteria    drug    p38    knockout    impaired    unknown    ribotoxin    fatal    mouse    investigation    powerful    hypothesize    mapkkk    organisms    integrity    cancer    cellular    activation    remedy    deficient    decades    refractory    inhibition    proximal    protein    rsr    underlying    therapy    initiate    infection    defective    human    team    impairment    pathological    lifespan    contributor    ricin    radiation    arising    presented    ribosomes    elucidate    inflammatory    jnk    contributes    yield    groups    mice    skin    critical    origins    surveys    irradiation    treat    relevance    physiological    line    triggered    phyrist    putative    encouraged    uv    ko    diverse    quality    am    nematodes    producing    cells    translation    activates    deregulation    cancers    implications    kinases    connections    molecular    ribotoxic    aging   

Project "PHYRIST" data sheet

The following table provides information about the project.

Coordinator
KOBENHAVNS UNIVERSITET 

Organization address
address: NORREGADE 10
city: KOBENHAVN
postcode: 1165
website: www.ku.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Total cost 1˙997˙678 €
 EC max contribution 1˙997˙678 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2019-COG
 Funding Scheme ERC-COG
 Starting year 2020
 Duration (year-month-day) from 2020-06-01   to  2025-05-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KOBENHAVNS UNIVERSITET DK (KOBENHAVN) coordinator 1˙997˙678.00

Map

 Project 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.

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The information about "PHYRIST" are provided by the European Opendata Portal: CORDIS opendata.

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