Projektbeschreibung
Der molekulare Ursprung der Aneuploidie
Eine fehlerhafte Chromosomentrennung während der Zellteilung führt zu einer abnormalen Chromosomenzahl. Dieser Zustand wird als Aneuploidie bezeichnet. Zu den Mechanismen, die diesem Mitosefehler zugrunde liegen, und der daraus resultierenden genomischen Instabilität bestehen jedoch Wissenslücken. Eine am EU-finanzierten Projekt ANEUPLOIDY beteiligte Forschungsgruppe möchte das Rätsel um diese molekularen Ereignisse, die zu genetischen Abweichungen führen, mithilfe von zellbiologischen, molekularbiologischen und biophysischen Methoden bei gesunden Organoiden und Krebs-Organoiden lösen. Das Team möchte die experimentelle Strategie um einen Modellierungsansatz ergänzen, um die Mechanismen der Mitosefehler mit der Genauigkeit der Chromosomentrennung in den Zellen zu verknüpfen. Die Ergebnisse werden Aufschluss über die Entstehung und Verbreitung von Mitosefehlern geben, die zu einer malignen Veränderung führen.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-SyG - Synergy grantGastgebende Einrichtung
10000 Zagreb
Kroatien