Description du projet
Un nouvel aperçu de l’assemblage des cils mobiles
De la fécondation à notre dernier souffle, les cils mobiles, de minuscules projections de microtubules à partir de la surface des cellules, sont essentiels à notre santé. Le mouvement des cils est alimenté par des masses de moteurs moléculaires appelés dynéines axonémales qui convertissent l’énergie en flexion des microtubules. Ces puissantes machines sont précisément assemblées à partir de nombreux composants différents. Ce projet CiliaCircuits financé par l’UE étudiera comment la cellule fabrique ces moteurs dans le temps et dans l’espace. Il vise à comprendre comment la cellule construit le nombre approprié de composants protéiques et les assemble dans le bon type de moteur. À long terme, on espère que CiliaCircuits identifiera de nouveaux interrupteurs moléculaires dans ce processus, menant à des thérapies efficaces pour les ciliopathies mobiles.
Objectif
Motile cilia are tiny microtubule-based projections which create fluid flow and are essential to human health. Cilia movement is powered by coordinated action of complex macromolecular motors, the axonemal dyneins. During differentiation, as cells produce hundreds of motile cilia, millions of dynein subunits must be pre-assembled in the cytoplasm into very large complexes in the correct stoichiometry which are then trafficked into growing cilia. This poses a sizeable challenge for the cell in terms of allocation of a significant fraction of the global translational machinery for streamlined assembly of dyneins within a crowded cellular space.
The key question remains: How does the cell know how much is enough? This is an extreme example of a common problem in cell biology. Responsive and adaptive mechanisms must exist to prevent futile expenditure of cellular resources in making a surplus of large molecules like dyneins that may also pose a risk of toxic aggregation. While a well-defined transcriptional code for induction of cilia motility genes exists, the translational dynamics and subsequent feedback circuitry coordinating dynein pre-assembly with ciliogenesis remain unexplored.
The molecular logic underlying the construction of motile cilia assembly are still not fully understood. The ambitious nature of CiliaCircuits proposes to use super-resolution and systems approaches to elucidate key mechanisms regulating this process in health and disease.
Human genetics tells us that making cilia motile is a complex process. To date, almost 40 genes have been implicated in primary ciliary dyskinesia (PCD), the disease of motile cilia, for which there is no cure. The long-term vision is to understand this dynamic control operating over a specialized proteome in time and space in order to develop effective PCD therapeutics and identify additional candidate genes involved in this translation regulation.
Champ scientifique
Not validated
Not validated
- natural sciencesbiological sciencesgenetics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicinemedical genetics
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
EH8 9YL Edinburgh
Royaume-Uni