Cell cycle regulation of polarity proteins in proliferating epithelia

增殖上皮细胞极性蛋白的细胞周期调节

基本信息

批准号：
10202913
负责人：
Katerina Ragkousi
金额：
$ 45.63万
依托单位：
AMHERST COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2025-02-28
项目状态：
未结题

项目摘要

PROJECT SUMMARY Epithelia are polarized layers of adherent cells and the first organized assemblies to emerge during animal development. As they constitute the scaffolds of most organs, they undergo extensive remodeling and proliferation throughout the life of the animal. A long-standing question is how proliferating cells maintain their epithelial organization. Loss of both cell cycle control and epithelial organization result in tissue deformations and epithelial cancers. Loss of cell polarity, in particular, is one of the most prevalent causes of epithelial disorganization. Our central hypothesis is that epithelial polarity is under cell cycle control. Work on proliferative epithelia of the sea anemone Nematostella vectensis has shown that polarity proteins oscillate on and off the apical domain in concert with the cell cycle. Discovery of similar polarity oscillations in various epithelia suggest that cell cycle regulation of epithelial polarity is broadly conserved. However, very little is known about the mechanisms that drive epithelial polarity oscillations and their role in tissue homeostasis. I propose to use the early developing embryos of Nematostella to investigate how the cell cycle regulates epithelial polarity. Nematostella embryos form polarized layers within the first few cleavages and maintain this organization during subsequent synchronous cell divisions. Imaging and molecular biological approaches will allow us to: [1] Dissect whether and how the cell cycle machinery directly modifies apical polarity proteins, and [2] Determine how mitotic changes in cytoskeletal organization control apical protein oscillations. The mechanisms we will uncover are likely to be broadly applicable in other animals and relevant for human epithelia and their associated diseases. .

项目概要上皮细胞是贴壁细胞的极化层，是动物生长过程中出现的第一个有组织的集合体。发展。由于它们构成了大多数器官的支架，因此它们经历了广泛的重塑和在动物的整个生命周期中增殖。一个长期存在的问题是增殖细胞如何维持其活性上皮组织。细胞周期控制和上皮组织的丧失导致组织变形和上皮癌。特别是细胞极性的丧失是上皮细胞异常的最常见原因之一。混乱。我们的中心假设是上皮极性受细胞周期控制。继续努力海葵 Nematostella vectensis 的增殖上皮细胞显示极性蛋白在并与细胞周期一致地离开顶端域。发现各种相似的极性振荡上皮细胞表明上皮极性的细胞周期调节广泛保守。然而，很少有了解驱动上皮极性振荡的机制及其在组织稳态中的作用。我提议利用 Nematostella 的早期发育胚胎来研究细胞周期如何调节上皮极性。线虫胚胎在最初的几次卵裂中形成极化层并维持这种状态随后同步细胞分裂期间的组织。成像和分子生物学方法将让我们能够：[1] 剖析细胞周期机制是否以及如何直接修饰顶端极性蛋白，以及 [2] 确定细胞骨架组织中的有丝分裂变化如何控制顶端蛋白振荡。这我们将发现的机制可能广泛适用于其他动物并与人类相关上皮细胞及其相关疾病。。