Descripción del proyecto
Información nueva sobre el ensamblaje de cilios móviles
Desde la fertilización hasta nuestro último aliento, los cilios móviles (unas minúsculas proyecciones microtubulares de la superficie de las células) son esenciales para nuestra salud. El movimiento de los cilios está impulsado por masas de motores moleculares, conocidos como dineínas axonemales, que convierten la energía en torsión de los microtúbulos. Estas potentes máquinas son el resultado del ensamblaje preciso de numerosos componentes diferentes. El proyecto financiado con fondos europeos CiliaCircuits investigará cómo fabrica la célula estos motores en el tiempo y el espacio. Su objetivo es comprender cómo construye la célula el número adecuado de componentes proteicos y los ensambla en el tipo de motor correcto. A largo plazo, el equipo de CiliaCircuits espera identificar novedosos conmutadores moleculares en este proceso para desarrollar tratamientos eficaces para las ciliopatías móviles.
Objetivo
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.
Ámbito científico
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
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
EH8 9YL Edinburgh
Reino Unido