Descripción del proyecto
Información molecular sobre el ensamblaje de los cilios de la superficie celular
Los cilios son prolongaciones minúsculas situadas en la superficie de células específicas, como los epitelios de las vías respiratorias, que ayudan al movimiento, la detección y la señalización. El mal funcionamiento de los cilios causa un grupo heterogéneo de enfermedades denominadas «ciliopatías». El proyecto CiliaTubulinCode, financiado con fondos europeos, tiene por objetivo comprender cómo se forman los cilios a partir de microtúbulos que constituyen una parte conservada del citoesqueleto de la célula. El trabajo se centra en las modificaciones postraslacionales y los isotipos de tubulina, el componente proteico de los microtúbulos. Los investigadores están estudiando la hipótesis de que este «código de la tubulina», como se lo conoce, impulsa el ensamblaje de los cilios, con lo que afecta a sus propiedades y función.
Objetivo
This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
20157 Milano
Italia