Descrizione del progetto
hSpindly quale regolatore del sistema per il checkpoint di assemblaggio del fuso
Il sistema per il checkpoint di assemblaggio del fuso (SAC, Spindle Assembly Checkpoint) degli eucarioti monitora il legame tra i microtubuli e i cinetocori, impedendo la separazione dei cromatidi fratelli nel corso della mitosi sino a che tutti i cromosomi si legano in modo corretto ai microtubuli del fuso e si allineano alla piastra metafasica. Recentemente, la nuova proteina Spindly è stata identificata quale regolatore specifico coinvolto nelle interazioni stabili tra microtubuli e cinetocori e nella progressione verso l’anafase. Il progetto SpinSAC, finanziato dall’UE, studierà i meccanismi alla base della funzione della Spindly umana (hSpindly, human Spindly) nella regolazione del SAC. La proteina hSpindly è altamente fosforilata nella mitosi e l’individuazione dei residui fosforilati contribuirà a chiarirne il ruolo svolto nella risposta cellulare ai farmaci antimitotici. Queste conoscenze sulla funzione della proteina hSpindly potrebbero portare all’identificazione di nuovi bersagli terapeutici per il trattamento dei tumori resistenti ai farmaci antimitotici.
Obiettivo
During mitosis a sophisticated surveillance system, known as the spindle assembly checkpoint (SAC), is crucial to make sure that the cell does not separate its sister chromatids until all the chromosomes are correctly attached to spindle microtubules and bi-oriented.
Nowadays, one of the more important strategy used for the cancer treatment is the inhibition of the microtubule dynamic to activate the SAC by the addition of anti-mitotic drugs. At the end, the activation of SAC for a long period provokes the cell death, compromising the tumour cell proliferation. Nonetheless, there are tumour cells, which are affected in SAC activity showing a reduction in the efficiency of this treatment. For this reason, it is becoming extremely useful to seek new proteins which are implicated directly to SAC functionality.
This project will be focused on the study of hSpindly as a new protein implicated in SAC regulation independently of the stripping pathway. hSpindly has a role in the SAC mechanism but how it works is absolutely unknown. hSpindly is highly phosphorylated in mitosis so, finding the residues which are phosphorylated in this cell cycle phase, will allow us to know not only the role of these phosphorylations in SAC but also its implication in the cell response in the presence of antimitotic drugs. For this, we will use several approaches and state of the art techniques as confocal microscopy and the CRISPR/Cas9 nickase system. This study will contribute with relevant results in basic and clinical research. The knowledge of the hSpindly function might reveal new therapeutic targets for the treatment of the tumours more resistant to anti-mitotic drugs. Additionally, it would be possible to get phosphospecific antibodies of key residues in the hSpindly function, which could be used as tumour marker in the future.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
41004 Sevilla
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