Descripción del proyecto
Información sobre la regulación de las chaperonas
La estructura correcta de las proteínas es indispensable para su funcionamiento, y su plegamiento anómalo se ha asociado con múltiples enfermedades, incluida la neurodegeneración. Las chaperonas moleculares ayudan a las proteínas a lograr su estructura natural, pero la regulación de su expresión no se comprende del todo. El objetivo del proyecto financiado con fondos europeos ChaperoneRegulome es dilucidar la regulación de los genes que codifican para las chaperonas en diferentes condiciones y requisitos de plegamiento de proteínas. La hipótesis de trabajo es que la concentración de chaperonas determina la susceptibilidad al plegamiento anómalo y depende del tipo de célula y de la cromatina. Los investigadores del proyecto combinarán métodos genéticos, informáticos y bioquímicos para aportar información sobre la regulación de la concentración de chaperonas.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
CB2 1TN Cambridge
Reino Unido