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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.

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

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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