Project description DEENESFRITPL Insight into the regulation of chaperones Proper conformation is paramount to protein function, and misfolding has been associated with various diseases, including neurodegeneration. Molecular chaperones help proteins achieve their native conformation, but the regulation of their expression is incompletely understood. The EU-funded ChaperoneRegulome project aims to delineate chaperone gene regulation under different conditions and protein folding demands. The working hypothesis is that chaperone levels determine the susceptibility to misfolding and depend on the type of cell and on chromatin. Through a combination of genetic, computational and biochemical approaches, researchers will provide insight into the regulation of chaperone levels. Show the project objective Hide the project objective Objective Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance. Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding Keywords molecular chaperones heat-shock proteins stress protein misfolding gene regulation Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-COG - ERC Consolidator Grant Call for proposal ERC-2018-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Net EU contribution € 1 992 500,00 Address TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge United Kingdom See on map Region East of England East Anglia Cambridgeshire CC Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 992 500,00 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE United Kingdom Net EU contribution € 1 992 500,00 Address TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge See on map Region East of England East Anglia Cambridgeshire CC Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 992 500,00 MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Participation ended Germany Net EU contribution € 0,00 Address HOFGARTENSTRASSE 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost No data