Project description
Not all cilia are created equal
Most of us think of motility when the word cilium is mentioned. Although motile cilia are very important to a few cell types like sperm or epithelial cells in the bronchi, non-motile (primary) cilia are found in almost all other cells and are intricately involved in sensing and signal transduction. It is only within the last several decades that we have started to realise the ubiquity and importance of these enigmatic organelles whose dysfunction has now earned its own classification, ciliopathies. The EU-funded DestCilia project will investigate primary cilia in both healthy and ciliopathy cell models to better understand their function in health and disease.
Objective
The primary cilium is a microtubule-based organelle that organizes a variety of cellular signaling pathways. Its importance for human health is illustrated by a large collection of cilium-based diseases, the ciliopathies, caused by mutations that alter cilium formation, structure, and function. Importantly, the mammalian Hedgehog signaling pathway is critically dependent on the primary cilium, dysregulation of which contributes to severe developmental defects and a variety of cancers. The ultimate goal of this work program is to enhance our understanding of the molecular mechanisms of ciliary signaling in health and disease. This is accomplished through the development of advanced technologies that provide a currently unattainable level of spatiotemporal control over ciliary proteins in mammalian cells. Unraveling the mechanisms by which the ciliary compartment orchestrates signal transduction is challenging, because ciliary and cytoplasmic roles of proteins involved in signal transduction are tightly connected, difficult to resolve and, importantly, context-specific. Here, an innovative chemical biology program is presented that provides a powerful toolbox to overcome these challenges, allowing the intraciliary manipulation, and therefore study, of ciliary proteins. Combining chemical probes, synthetic ciliary targeting approaches, and a modular enzymatic tagging strategy, this program provides unprecedented opportunities to probe, visualize, inhibit or degrade proteins at specific times and selectively within the ciliary compartment. Specifically, these tools will be used to decipher the relationships between tubulin acetylation state, intraflagellar transport, and Hedgehog signal transduction in wild-type and ciliopathy-mutant cells. These innovative work packages synergistically provide enhanced fundamental understanding of ciliary signaling, and pave the way for novel therapeutic approaches to combat cilium-based diseases.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
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Funding Scheme
ERC-STG - Starting GrantHost institution
1211 Geneve
Switzerland