H2020Индивидуална стипендия2020–2022

CENTROMD · Deciphering the molecular dynamics of centriole and centrosome biogenesis

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-12-01 → 2022-11-30
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Молекулярната динамика на центриолите и центрозомите се проучва чрез наблюдение на протеини в ембриони на плодови мухи. Разбирането на тези процеси помага при изследването на рака, затлъстяването и микроцефалията, тъй като нарушенията в тези структури са свързани с тези заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Deciphering the molecular dynamics of centriole and centrosome biogenesis

Centrioles are cellular structures that form two key organelles: the centrosome, composed of a centriole pair surrounded by the pericentriolar matrix (PCM), and the basal body, which forms the cilium, an intricate structure that is essential for cell motility and environment sensing. Centrosomes and cilia perform many important functions in animal cells and their dysfunction is associated with an extensive array of pathologies, including cancer, dwarfism, microcephaly and obesity. Centrosome amplification (CA) constitutes an abnormal numerical increase in centrosome numbers, and can arise due to centriole overduplication during the cell cycle. CA has been reported in nearly all solid or hematologic human cancers, and can by itself lead to tumorigenesis. Elucidating the mechanisms that regulate centriole and centrosome biogenesis is of paramount importance for cell biology and cancer research. The aim of this action was to investigate the dynamic behaviour of key players involved in centrosome and centriole biogenesis, using cutting-edge super-resolution microscopy and the Drosophila embryo as an in vivo model. Centrioles organize the PCM, a complex protein machine that has many functions and that assembles/disassembles very quickly. The molecular principles that allow such a complex machine to undergo drastic variations in size are unclear but it is evident that proper centrosome size is important for mitotic fidelity. Although many hundreds of proteins localise to centrosomes, only Cnn, Spd-2 and Polo kinase (the Drosophila homologues of human Cdk5Rap2,CEP192 and Plk1, respectively) are essential for the assembly of the mitotic PCM in flies. We developed and implemented methods to characterise the behavior of individual molecules of Spd2 and Cnn as they move through the PCM and found that these are incorporated at the centre close to the centriole and gradually flux outwards. In general terms, we found that molecules flux slower when the centrosome is growing in preparation for mitosis and faster when the target size has been reached and that flux is influenced by microtubule pulling on the PCM, phosphorylation of Cnn and Spd2 and from constant incorporation of new molecules at the surface of the centriole generating a pushing motion. Our findings indicate that flux dynamics of individual key components underlie the growth of the centrosome to its correct size in preparation for mitosis.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Centrosomes are organelles composed of a pair of centrioles surrounded by a pericentriolar matrix (PCM) that perform a variety of key functions in the animal cell. Centrosomes duplicate precisely once during S-phase of the cell cycle; in G2-phase the two centrosomes move to opposite locations around the nucleus and expand their PCM to nucleate vast quantities of microtubules for mitotic spindle formation. Dysfunctions in the centrosome cycle have been associated with a wide range of pathologies and, in particular, centrosome amplification, an aberrant increase in centrosome numbers, is a hallmark of most human cancers. Centrosomes are complex machines composed of hundreds of proteins, however significant efforts over the past decades have identified the key elements which are essential for centriole and centrosome biogenesis. We can now address the molecular mechanisms that mediate interactions between key players and how these contribute to regulate the number and size of these organelles during the cell cycle. Elucidating these mechanisms is of great interest to cell biology and cancer research. This research proposal aims to investigate aspects of centriole and centrosome biogenesis using Drosophila melanogaster as an animal model. The main objectives are: 1), to reconstitute initial steps of centriole assembly using a hybrid in vivo/in vitro approach, where I will study the molecular dynamics of the interaction between key centriolar proteins Asl and Plk4, using functionalised microspheres as a scaffold and 2), to analyse the dynamic behaviour of single molecules of key centrosomal proteins Cnn and Spd-2 as they move throughout the PCM during expansion, using super-resolution microscopy techniques. We are confident that these studies will provide novel insights into the design principles and inner workings of these important organelles.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordКоординаторОбединеното кралство