Shaping The Nucleus, For Better Or Worse

塑造核心，无论好坏

• 批准号: BB/Y004205/1
• 负责人: Monica Agromayor
• 金额: $ 82.67万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY004205%2F1
• 关键词: Shaping; Nucleus; Better; Worse

The nucleus is the cellular organelle that contains the genetic material. This compartment is surrounded by a double membrane known as the nuclear envelope, that allows the controlled exchange of material with the cytoplasm. The traditional view has been that the nuclear envelope is a passive barrier that mostly protects the genome and allows gene expression. However, we now know that under certain conditions, such as exposure to physical forces, cells can experience mechanical stress that deforms the nucleus. These deformations of the nuclear envelope can initiate signalling pathways that induce changes in gene expression and cellular behaviour. On the contrary, extreme deformations can lead to rupture of the nuclear envelope and genomic instability. We therefore need to know the relationship between nuclear deformations and cellular function. This project will answer this question by combining molecular and cell biology approaches with advanced quantitative microscopy and biophysics. We will build on our recent work identifying factors that regulate the shape of the nuclear envelope, thus allowing the selective perturbation of shape control. Specifically, we will elucidate i) what type of NE deformation constitutes a physiological signal or a pathological perturbation ii) the ultrastructure and dynamics of NE under stress iii) how NE deformations influence physiological functions such as the cellular adaptations to physical confinement and mechanical stress. This fundamental knowledge may inform new mechanisms of disease, from cardiopathies to cancer.

细胞核是含有遗传物质的细胞器。这个隔室被称为核膜的双层膜所包围，它允许与细胞质进行受控的物质交换。传统观点认为，核膜是一种被动屏障，主要保护基因组并允许基因表达。然而，我们现在知道，在某些条件下，例如暴露在物理力量下，细胞可能会经历使细胞核变形的机械应力。核膜的这些变形可以启动信号通路，导致基因表达和细胞行为的变化。相反，极端的变形会导致核膜的破裂和基因组的不稳定。因此，我们需要知道核变形和细胞功能之间的关系。这个项目将通过将分子和细胞生物学方法与先进的定量显微镜和生物物理学相结合来回答这个问题。我们将在最近工作的基础上确定调节核包膜形状的因素，从而允许形状控制的选择性扰动。具体地说，我们将阐明：1)什么类型的NE变形构成生理信号或病理扰动；2)应激下NE的超微结构和动力学；3)NE变形如何影响生理功能，如细胞对物理限制和机械应力的适应。从心脏病到癌症，这些基础知识可能会为疾病的新机制提供信息。