Description du projet
Un aperçu de la régulation des chaperons
Une conformation adaptée est essentielle au fonctionnement protéique, et le mauvais repliement a été associé à plusieurs maladies, notamment la neurodégénérescence. Les chaperons moléculaires aident les protéines à parvenir à leur conformation native, mais la régulation de leur expression reste mal comprise. Le projet ChaperoneRegulome, financé par l’UE, entend délimiter la régulation génétique des chaperons sous des conditions et des exigences de repliement protéique différentes. L’hypothèse de travail étant que les niveaux de chaperons déterminent la prédisposition au repliement et dépendent du type de cellule ainsi que de la chromatine. À travers une combinaison d’approches génétiques, informatiques et biochimiques, les chercheurs fourniront des informations sur la régulation des niveaux de chaperons.
Objectif
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.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
CB2 1TN Cambridge
Royaume-Uni