Project description
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.
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
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
CB2 1TN Cambridge
United Kingdom