Descrizione del progetto
Uno sguardo alla regolazione degli chaperone molecolari
Una conformazione corretta è fondamentale per la funzione delle proteine e il loro errato ripiegamento è stato associato a varie malattie, compresa la neurodegenerazione. Gli chaperone molecolari aiutano le proteine a raggiungere la loro conformazione nativa ma la regolazione della loro espressione non è del tutto chiara. Il progetto ChaperoneRegulome, finanziato dall’UE, intende delineare la regolazione dei geni chaperone in diverse condizioni e richieste di ripiegamento proteico. L’ipotesi di lavoro è che i livelli degli chaperone molecolari determinino la suscettibilità al ripiegamento errato e dipendano dal tipo di cellula e dalla cromatina. Attraverso una combinazione di approcci genetici, computazionali e biochimici, i ricercatori approfondiranno la regolazione dei livelli di chaperone.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
CB2 1TN Cambridge
Regno Unito