Descrizione del progetto
Indizi molecolari sull’assemblaggio delle ciglia presenti sulla superficie cellulare
Le ciglia sono piccole sporgenze presenti sulla superficie di cellule specifiche, come l’epitelio delle vie respiratorie, che forniscono assistenza per attività quali il movimento, il rilevamento e la segnalazione. La disfunzione di questi organuli provoca un gruppo eterogeneo di malattie note come ciliopatie. Il progetto CiliaTubulinCode, finanziato dall’UE, è interessato a comprendere il modo in cui le ciglia si formano a partire dai microtubuli, che costituiscono una parte conservata del citoscheletro cellulare. Il lavoro concentra l’attenzione sulle modifiche post-traslazionali e sugli isotopi della tubulina, il componente proteico dei microtubuli. I ricercatori stanno approfondendo l’ipotesi secondo cui questo «codice della tubulina», secondo l’espressione con cui è noto, guiderebbe l’assemblaggio delle ciglia, influenzandone le proprietà e la funzione.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
20157 Milano
Italia