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UPR NEURO SIGNED

The Unfolded Protein Response in Neurodegeneration

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EC-Contrib. €

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Project "UPR NEURO" data sheet

The following table provides information about the project.

Coordinator
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE 

Organization address
address: TRINITY LANE THE OLD SCHOOLS
city: CAMBRIDGE
postcode: CB2 1TN
website: www.cam.ac.uk

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 United Kingdom [UK]
 Total cost 1˙979˙286 €
 EC max contribution 1˙979˙286 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-09-01   to  2020-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE UK (CAMBRIDGE) coordinator 1˙979˙286.00

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 Project objective

This proposal aims to increase our understanding of the role of translational failure in human neurodegenerative diseases. We recently discovered the mechanism by which protein misfolding leads to neurodegeneration in prion disease. The pathway involved is a generic cellular pathway, a branch of the unfolded protein response (UPR) that controls protein synthesis at the level of initiation of translation. Rising levels of misfolded prion protein cause sustained over-activation of the PERK-eIF2α branch of the UPR in neurons resulting in an uncompensated decline in global translation rates, synaptic failure and neuronal death. Reduction of eIF2α-P levels by genetic manipulation or by pharmacological inhibition of PERK, rescue vital translation rates and prevent neurodegeneration and clinical disease in prion-infected mice. There is increasing evidence that UPR dysregulation is a central process in protein misfolding neurodegenerative diseases, and that maintaining translation levels is essential for neuronal health. Raised levels of PERK-P and eIF2α-P occur in brains of patients with Alzheimer’s (AD), Parkinson’s (PD), and related diseases. The pathway is also implicated in learning and memory; manipulation of eIF2α-P levels boost cognition in wild type mice and restore memory deficits in AD mouse models. We will test for over-activation of PERK/eIF2α-P and the effects of its manipulation in other models of neurodegenerative disease. We will generate new transgenic mouse models that isolate translational failure from specific misfolded proteins and use these to gain valuable new insights into the window for intervention when neurons can still be rescued, the selective vulnerability of different neuronal populations, and the role of the UPR in neurons and glia. Collectively, the aim is to increase insight into the role of UPR-mediated translational failure in human neurodegenerative disease and determine its tractability for the treatment of dementia.

 Publications

year authors and title journal last update
List of publications.
2015 Helois Radford, Julie A. Moreno, Nicholas Verity, Mark Halliday, Giovanna R. Mallucci
PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia
published pages: 633-642, ISSN: 0001-6322, DOI: 10.1007/s00401-015-1487-z
Acta Neuropathologica 130/5 2020-01-17
2016 Heather L. Smith, Giovanna R. Mallucci
The unfolded protein response: mechanisms and therapy of neurodegeneration
published pages: 2113-2121, ISSN: 0006-8950, DOI: 10.1093/brain/aww101
Brain 139/8 2020-01-17
2017 Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, Andrew B. Tobin
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
published pages: 487-499, ISSN: 0021-9738, DOI: 10.1172/JCI87526
Journal of Clinical Investigation 127/2 2020-01-17
2018 Lisa Michelle Restelli, Björn Oettinghaus, Mark Halliday, Cavit Agca, Maria Licci, Lara Sironi, Claudia Savoia, Jürgen Hench, Markus Tolnay, Albert Neutzner, Alexander Schmidt, Anne Eckert, Giovanna Mallucci, Luca Scorrano, Stephan Frank
Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21
published pages: 1407-1414, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.07.023
Cell Reports 24/6 2020-01-17
2017 Mark Halliday, Daniel Hughes, Giovanna R. Mallucci
Fine-tuning PERK signaling for neuroprotection
published pages: 812-826, ISSN: 0022-3042, DOI: 10.1111/jnc.14112
Journal of Neurochemistry 142/6 2020-01-17
2016 Oliver J. Freeman, Giovanna R. Mallucci
The UPR and synaptic dysfunction in neurodegeneration
published pages: 530-537, ISSN: 0006-8993, DOI: 10.1016/j.brainres.2016.03.029
Brain Research 1648 2020-01-17
2017 Mark Halliday, Helois Radford, Karlijn A. M. Zents, Collin Molloy, Julie A. Moreno, Nicholas C. Verity, Ewan Smith, Catharine A. Ortori, David A. Barrett, Martin Bushell, Giovanna R. Mallucci
Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
published pages: 1768-1783, ISSN: 0006-8950, DOI: 10.1093/brain/awx074
Brain 140/6 2020-01-17
2016 I Celardo, A C Costa, S Lehmann, C Jones, N Wood, N E Mencacci, G R Mallucci, S H Y Loh, L M Martins
Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease
published pages: e2271, ISSN: 2041-4889, DOI: 10.1038/cddis.2016.173
Cell Death and Disease 7/6 2020-01-17

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