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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.

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

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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