Description du projet
L’origine moléculaire de l’aneuploïdie
Les erreurs de ségrégation des chromosomes pendant la division cellulaire conduisent à un nombre anormal de chromosomes, un trouble connu sous le nom d’aneuploïdie. Les connaissances actuelles se révèlent insuffisantes pour comprendre les mécanismes qui sous-tendent ces erreurs mitotiques et comment ils provoquent une instabilité génomique. Pour dévoiler les événements moléculaires qui conduisent à des anomalies génomiques, les scientifiques du projet ANEUPLOIDY financé par l’UE appliqueront des méthodologies de biologie cellulaire, de biologie moléculaire et de biophysique à des organoïdes sains et cancéreux. Ils prévoient de compléter la stratégie expérimentale par une approche de modélisation pour relier les mécanismes des erreurs mitotiques à la fidélité de ségrégation chromosomique dans les cellules. Les résultats éclaireront la façon dont les erreurs mitotiques émergent et se propagent, conduisant à une transformation maligne.
Objectif
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.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-SyG - Synergy grantInstitution d’accueil
10000 Zagreb
Croatie