Summary
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.
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| Web resources: | https://cordis.europa.eu/project/id/948750 |
| Start date: | 01-01-2021 |
| End date: | 31-12-2025 |
| Total budget - Public funding: | 1 408 776,00 Euro - 1 408 776,00 Euro |
Cordis data
Original description
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.Status
SIGNEDCall topic
ERC-2020-STGUpdate Date
27-04-2024
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