Descrizione del progetto
L’origine molecolare dell’aneuploidia
Gli errori nella segregazione cromosomica durante la divisione cellulare conducono ad un numero anomalo di cromosomi, una condizione nota come aneuploidia. V’è una scarsa conoscenza sui meccanismi alla base di questi errori mitotici e sul modo in cui causano instabilità genomica. Per svelare gli eventi molecolari che conducono ad anomalie genomiche, gli scienziati del progetto ANEUPLOIDY, finanziato dall’UE, applicheranno la biologia cellulare, la biologia molecolare e le metodologie di biofisica ad organoidi tumorali e sani. Essi pianificano di complementare la strategia sperimentale con un approccio di modellazione per collegare i meccanismi degli errori mitotici alla fedeltà della segregazione cromosomica nelle cellule. I risultati faranno luce sul modo in cui gli errori mitotici si presentano e si diffondono, conducendo a una trasformazione maligna.
Obiettivo
Chromosome segregation errors cause aneuploidy, a state of karyotype imbalance that accelerates tumor formation and impairs embryonic development. Even though mitotic errors have been studied extensively in cell cultures, the mechanisms generating various errors, their propagation and effects on genome integrity are not well understood. Moreover, very little is known about mitotic errors in complex tissues. The main goal of this project is to uncover the molecular origins of mitotic errors and their contribution to karyotype aberrations in healthy and diseased tissues. To achieve our goal, we have assembled an interdisciplinary team of experts in molecular and cell biology, cell biophysics, chromosomal instability in cancer, and theoretical physics. Our team will introduce novel approaches to study aneuploidy (superresolution microscopy, optogenetics, laser ablation, single cell karyotype sequencing) and apply them to state-of-the-art tissue cultures (mammalian organoids and tumoroids). In close collaboration, Tolić will establish assays to detect and quantify error types in cells, and Kops and Amon will use the assays on various healthy and cancer tissues. Tolić and Kops will uncover the molecular origins of errors, their propagation and impact on genome integrity, while Amon will lead the investigation of the mechanisms that ensure high chromosome segregation fidelity in healthy tissues. Interwoven in these collaborations are the efforts of Pavin, who will develop a theoretical model to describe the origin of errors and to quantitatively link chromosome segregation fidelity in single cells and tissues. Model and experiment will continuously inspire each other, to achieve deep understanding of how mitotic errors arise, how they propagate and how they impact on cell populations. Thus, the extensive sets of expertise present in our team will be combined and expanded with novel technologies to tackle the big challenge of the origins of aneuploidy in humans.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-SyG - Synergy grantIstituzione ospitante
10000 Zagreb
Croazia