Descripción del proyecto
El origen molecular de las aneuploidías
Los errores en la segregación de cromosomas durante la división celular provocan un número anómalo de cromosomas, una afección denominada aneuploidía. Por el momento, se desconocen los mecanismos subyacentes a estos errores mitóticos y el modo en que provocan inestabilidad genómica. Para esclarecer los sucesos moleculares que producen anomalías genómicas, científicos del proyecto financiado con fondos europeos ANEUPLOIDY aplicarán metodologías de biología celular, biología molecular y biofísica en organoides cancerosos y sanos. Tienen previsto complementar la estrategia experimental con un enfoque de modelización para establecer un vínculo entre los mecanismos de los errores mitóticos y la fidelidad de la segregación de cromosomas en las células. Los resultados arrojarán luz sobre cómo se producen y se propagan los errores mitóticos hasta dar lugar a una transformación maligna.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Tema(s)
Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
10000 Zagreb
Croacia