Biophysical regulation of nucleolar structure and function in cellular senescence and ageing

随着身体组织的老化，它们会逐渐积累功能失调的衰老细胞，这些细胞无法增殖，导致组织健康的年龄相关性下降。衰老细胞的特征是大量的生化和结构变化，包括细胞核内DNA和核仁的重塑。由于核仁是生产核糖体和调节蛋白质合成的中心，在衰老过程中其正常结构和功能的破坏可能会导致细胞和组织衰老。我们团队和其他人最近的研究也表明，核仁和周围DNA之间的物理相互作用控制着核仁的结构和细胞合成核糖体和蛋白质的能力。因此，我们提出，在衰老过程中，细胞的物理和机械性质发生了巨大的变化，这些变化调节了核仁的结构和功能，并导致了细胞和组织健康中与年龄相关的缺陷。在这个项目中，我们计划研究细胞和核仁的物理性质在衰老过程中如何改变，以及核仁的结构变化如何影响细胞代谢和组织衰老。我们将重点关注皮肤作为一个模型系统，并使用最先进的生物物理工具来表征健康和衰老皮肤细胞的机械特性。此外，我们将使用分子图谱方法来确定基因表达和蛋白质合成的相应变化。然后，我们将用健康和衰老的细胞构建3D合成皮肤模型，并研究核仁的物理属性如何影响这些组织模型的功能。最后，我们将把这些发现和反应与从年轻和老年捐赠者身上获得的皮肤样本进行比较。这些研究将首次确定衰老细胞核内发生的生物物理变化以及对核仁基本功能的影响。这些发现将为细胞衰老和衰老的基本过程提供新的线索，这项工作将为促进健康老龄化开辟新的机会。

As tissues in the body age, they progressively accumulate dysfunctional senescent cells, which are unable to proliferate and contribute to the age-related decline in tissue health. Senescent cells are characterised by numerous biochemical and structural changes, including remodelling of DNA and nucleoli within the nucleus. As the nucleoli are central hubs for production of ribosomes and the regulation of protein synthesis, disruption of their normal structure and function during senescence could contribute to cell and tissue ageing.Recent studies by our team and others have also shown that physical interactions between the nucleoli and surrounding DNA control the structure of nucleoli and the cell's ability to synthesise ribosomes and protein. We therefore propose that during senescence cells undergo dramatic changes in their physical and mechanical properties, which regulate the structure and function of the nucleoli and contribute to age-related defects in cell and tissue health.In this project we plan to investigate how the physical properties of the cell and nucleoli become altered during senescence and how structural changes in the nucleoli impact on cell metabolism and tissue ageing. We will focus on the skin as a model system and employ state-of-the-art biophysical tools to characterise the mechanical properties of healthy and senescent skin cells. In addition, we will use molecular profiling methods to determine the corresponding changes in gene expression and protein synthesis. We will then construct 3D synthetic skin models with healthy and senescent cells and investigate how the physical properties of the nucleoli influence the function of these tissue models. Finally, we will compare these findings and responses to those of skin samples obtained from young and old donors.Together, these studies will define for the first time the biophysical changes that occur within the nucleus of senescent cells and the impact on the essential functions of the nucleolus. The findings will shed new light on the fundamental process of cellular senescence and ageing, and the work will open up new opportunities for promoting healthy ageing.