Projektbeschreibung
Einblick in die Zusammensetzung motiler Zilien
Motile Zilien, also winzige, auf Mikrotubuli aufbauende Projektionen von der Zelloberfläche spielen von der Befruchtung bis zu unserem letzten Atemzug eine entscheidende Rolle für unsere Gesundheit. Die Bewegung der Zilien wird durch Massen von molekularen Motoren angetrieben, die als axonemale Dyneine bekannt sind. Sie wandeln Energie in die Biegung der Mikrotubuli um. Diese mächtigen Maschinen werden aus verschiedenen Komponenten präzise zusammengesetzt. Das EU-finanzierte Projekt CiliaCircuits wird untersuchen, wie die Zelle diese Motoren zeitlich und räumlich produziert. Dabei soll geklärt werden, wie sie die entsprechende Zahl von Proteinkomponenten erzeugt und in den richtigen Motortypen zusammenfügt. Auf lange Sicht wird CiliaCircuits hoffentlich neue molekulare Schalter in diesem Prozess finden, woraus sich dann effektive Therapeutika für motile Ziliopathien ergeben könnten.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesgenetics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicinemedical genetics
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
EH8 9YL Edinburgh
Vereinigtes Königreich