PRIMES

PRIMES: Protein interaction machines in oncogenic EGF receptor signalling

 Coordinatore UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN 

 Organization address address: BELFIELD
city: DUBLIN
postcode: 4

contact info
Titolo: Mr.
Nome: Donal
Cognome: Doolan
Email: send email
Telefono: +353 1 716 1656
Fax: +353 1 716 1216

 Nazionalità Coordinatore Ireland [IE]
 Totale costo 15˙993˙777 €
 EC contributo 11˙999˙640 €
 Programma FP7-HEALTH
Specific Programme "Cooperation": Health
 Code Call FP7-HEALTH-2011-two-stage
 Funding Scheme CP-IP
 Anno di inizio 2011
 Periodo (anno-mese-giorno) 2011-12-01   -   2016-11-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN

 Organization address address: BELFIELD
city: DUBLIN
postcode: 4

contact info
Titolo: Mr.
Nome: Donal
Cognome: Doolan
Email: send email
Telefono: +353 1 716 1656
Fax: +353 1 716 1216

IE (DUBLIN) coordinator 2˙226˙380.00
2    UPPSALA UNIVERSITET

 Organization address address: SANKT OLOFSGATAN 10 B
city: UPPSALA
postcode: 751 05

contact info
Titolo: Prof.
Nome: Erik
Cognome: Ullerås
Email: send email
Telefono: +46 18 471 4493
Fax: +46 18 47 14868

SE (UPPSALA) participant 1˙186˙998.00
3    VICHEM CHEMIE KUTATO KFT

 Organization address address: HERMANN OTTO UTCA 15
city: BUDAPEST
postcode: 1022

contact info
Titolo: Mr.
Nome: Zoltán
Cognome: Dobai
Email: send email
Telefono: +36 1 4872080
Fax: +36 1 7999990

HU (BUDAPEST) participant 1˙000˙110.00
4    EBERHARD KARLS UNIVERSITAET TUEBINGEN

 Organization address address: GESCHWISTER-SCHOLL-PLATZ
city: TUEBINGEN
postcode: 72074

contact info
Nome: Christine
Cognome: Augustin
Email: send email
Telefono: +49 7071 29 84021
Fax: +49 7071 294560

DE (TUEBINGEN) participant 980˙000.00
5    KUNGLIGA TEKNISKA HOEGSKOLAN

 Organization address address: Valhallavaegen 79
city: STOCKHOLM
postcode: 10044

contact info
Titolo: Mr.
Nome: åke
Cognome: Eriksson
Email: send email
Telefono: +46 8 5537 8288
Fax: +46 8 5537 8056

SE (STOCKHOLM) participant 893˙440.00
6    MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.

 Organization address address: Hofgartenstrasse 8
city: MUENCHEN
postcode: 80539

contact info
Titolo: Ms.
Nome: Barbara
Cognome: Dobruchowski
Email: send email
Telefono: +49 231 133 2507
Fax: +49 231 133 2595

DE (MUENCHEN) participant 885˙750.00
7    The Beatson Institute for Cancer Research

 Organization address address: "GARSCUBE ESTATE, SWITCHBACK ROAD"
city: GLASGOW
postcode: G61 1BD

contact info
Titolo: Mr.
Nome: Peter David
Cognome: Winckles
Email: send email
Telefono: +44 141 331 6211

UK (GLASGOW) participant 853˙000.00
8    FUNDACIO CENTRE DE REGULACIO GENOMICA

 Organization address address: CARRER DOCTOR AIGUADER 88
city: BARCELONA
postcode: 8003

contact info
Titolo: Mr.
Nome: Stefan
Cognome: Ponisch
Email: send email
Telefono: +34 933160264
Fax: 34933969983

ES (BARCELONA) participant 833˙440.00
9    THE UNIVERSITY OF EDINBURGH

 Organization address address: OLD COLLEGE, SOUTH BRIDGE
city: EDINBURGH
postcode: EH8 9YL

contact info
Titolo: Ms.
Nome: Angela
Cognome: Noble
Email: send email
Telefono: +44 131 650 9024
Fax: +44 131 650 9023

UK (EDINBURGH) participant 810˙300.00
10    JOHANN WOLFGANG GOETHE UNIVERSITAET FRANKFURT AM MAIN

 Organization address address: GRUNEBURGPLATZ 1
city: FRANKFURT AM MAIN
postcode: 60323

contact info
Titolo: Ms.
Nome: Mareike
Cognome: Schmitt
Email: send email
Telefono: +49 69 79825194
Fax: +49 69 79825007

DE (FRANKFURT AM MAIN) participant 766˙560.00
11    THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

 Organization address address: University Offices, Wellington Square
city: OXFORD
postcode: OX1 2JD

contact info
Titolo: Dr.
Nome: Stephen
Cognome: Conway
Email: send email
Telefono: +44 1865 289800
Fax: +44 1865 289801

UK (OXFORD) participant 753˙996.00
12    South Australian Health and Medical Research Institute

 Organization address address: 121 KING WILLIAM STREET LEVEL 9
city: ADELAIDE
postcode: 5000

contact info
Titolo: Prof.
Nome: Terence
Cognome: Dear
Email: send email
Telefono: +61088116 4435

AU (ADELAIDE) participant 499˙999.00
13    TEAGASC - AGRICULTURE AND FOOD DEVELOPMENT AUTHORITY

 Organization address address: Oak Park
city: CARLOW

contact info
Titolo: Ms.
Nome: Dowling
Cognome: Anne
Email: send email
Telefono: +353 46 9061103
Fax: +353 46 9061105

IE (CARLOW) participant 309˙667.00
14    THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO

 Organization address address: KINGS COLLEGE CIRCLE 27
city: TORONTO
postcode: M5S 1A1

contact info
Titolo: Prof.
Nome: Igor
Cognome: Stagljar
Email: send email
Telefono: +1 416 946 7828
Fax: +1 416 978 8287

CA (TORONTO) participant 0.00

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

mamth    crc    interaction    genetic    pathogenetic    biological    colorectal    tissues    compounds    mouse    mechanisms    interactions    rates    affect    chemical    dynamic    signalling    resistance    egfr    therapies    machines    drugs    drug    network    imaging    therapeutic    poor    receptor    molecular    components    erbb    cancer    protein    mathematical    proteins    validated    networks    models    oncogenic    specificity    functional    static    responses    proteomics    outcome    primes    efficacious    scientists    human   

 Obiettivo del progetto (Objective)

'PRIMES focuses on the role of protein interactions to assemble dynamic molecular machines that receive and process information to coordinate cellular responses. PRIMES investigates the following: (i) How do protein interactions contribute to the generation of biological specificity in signalling? (ii) How do pathogenetic perturbations affect protein interaction networks? (iii) How can we exploit protein interactions as therapeutic targets? We focus on the EGFR/ERBB signalling network and its role in colorectal cancer (CRC), the third most frequent cancer. The ERBB network is frequently altered in CRC either through overexpression or mutation of the receptors or downstream components. Network components have become important drug targets. Poor response rates and resistance demonstrate we lack sufficient insight to design efficacious therapies. Using proteomics, structural biology, advanced imaging and mathematical modelling we (i) map static and dynamic protein interactions in the ERBB network (ii) unravel the design principles and emergent network properties conferred by protein interactions; and (iii) validate these findings in genetic mouse models of CRC and human tissues. PRIMES aims to (i) enhance the functional pathogenetic understanding of CRC (ii) identify mechanisms of drug resistance and drug efficacy; and (iii) identify drugs that affect protein interactions to rationally manipulate network functions related to individual genetic mutations. Outcomes include (i) a dynamic, mechanistic flowchart of how protein interactions compute biochemical and biological specificity in signalling networks (ii) a functional protein interaction network of healthy and oncogenic ERBB signalling validated in mouse models of CRC and human tissues (iii) network level insights towards personalised CRC treatment based on genotype-phenotype relationships; and (iv) chemical compounds targeting protein interactions to restore normal ERBB network function or break oncogenic circuits.'

Introduzione (Teaser)

Deconstructing the molecular interactions in cancer cells could lead to the discovery of novel drug targets. A European consortium is looking at how the dynamic interactions among proteins drive oncogenic signalling.

Descrizione progetto (Article)

The epidermal growth factor receptor (EGFR/ErbB) regulates key developmental processes including cell proliferation and differentiation. Aberrant EGFR signalling is encountered in many cancers suggesting that it may play a central role in disease onset or progression.

The EU-funded 'Protein interaction machines in oncogenic EGF receptor signalling' (http://www.primes-fp7.eu/ (PRIMES)) study focuses on the role of EGFR signalling in colorectal and breast cancer and in particular on protein interactions. Researchers will employ a combination of techniques including fluorescence imaging, proteomics and mathematical modelling. They aim to analyse both static and dynamic protein interactions within the EGFR pathway and elucidate their role.

The PRIMES experimental outline entails the use of natural ligands or drugs to perturb signalling. The functional outcome is observed using imaging microscopy and proteomics. Similar experiments will be performed by interfering with the expression of particular network proteins.

The work so far has led to the delineation of an interactive network of 55 proteins. Scientists developed the Mammalian Membrane Two-Hybrid (MaMTH) method to identify receptor-interacting partners including novel players in oncogenic EGFR signalling. MaMTH demonstrated low false negative rates and facilitated the monitoring of protein-protein interactions. Receptor modifiers have also been identified and their role in modulating EGFR responses is being evaluated. To predict the outcome of protein interactions and recapitulate the EGFR network, scientists are developing suitable assays and mathematical models.

To add clinical relevance to the work, project findings will be validated in cancer mouse models and patient samples. From a therapeutic perspective, the PRIMES consortium will identify chemical compounds that target protein interactions via different mechanisms through high-throughput screening of small compound libraries.

The PRIMES study will significantly improve our knowledge on the role of protein interactions as signal processing machines in cancer. Equally importantly, the project deliverables will help design new, efficacious, targeted therapies to overcome the poor therapeutic responses and resistance observed with traditional drugs.

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