Control of rDNA damage and the potentiation of cGAS-STING mediated immune signals

这个项目是多发病、预防和早期发现的交叉点。老龄化增加了患心血管疾病、癌症、糖尿病和神经变性的风险，这些疾病降低了生活质量，限制了生命。重要的是，这些疾病在人群中的严重程度和外显率的变化表明我们的生物年龄。该项目旨在揭示rDNA重复序列的稳定性和生物老化之间的紧密联系的机制。与衰老相关的疾病，如心血管疾病、神经退行性疾病、糖尿病和癌症，在人群中的严重程度和发生率各不相同，这表明时间衰老与生物年龄不同，可能是由于遗传和环境的原因。遗传综合征和生活方式可以通过增加DNA损伤或减少DNA修复来影响细胞生物老化。有缺陷的DDR信号主要通过增加常见脆弱位点、端粒和核糖体rDNA重复序列（rDNA）的复制压力来驱动基因组不稳定，rDNA重复序列由于其重复性难以复制。因此，调控rDNA的能力降低可能导致基因组不稳定性增加。除了难以复制外，rDNA重复序列对外源DNA损伤很敏感，受损重复序列的逐渐丢失被认为是维持基因组稳定性的一种机制。响应DNA损伤的rDNA重复序列的丢失与细胞适应性下降和衰老有关。生活方式暴露于增加DNA复制压力（环境）或无法修复内源性DNA损伤（遗传/表观遗传）的物质中，可能优先诱导rDNA重复数减少，这可能通过降低细胞和组织适应性与生物衰老有关。一般来说，酵母模型很好地描述了DNA损伤与rDNA丢失与寿命的关联，本研究旨在解决这一机制在哺乳动物衰老和癌症中同样起作用的假设。

This project is at the intersection of Multimorbidities and Prevention and early detection. Ageing increases the risk of cardiovascular disease, cancer, diabetes and neurodegeneration, which reduce quality of life and are life-limiting. Importantly, variation in severity and penetrance of these disorders across the population indicates that our biological age. This project seeks to unravel the mechanism of the strong links between the stability of rDNA repeats and biological ageing.Ageing associated conditions such cardiovascular disease, neurodegeneration, diabetes and cancer, vary in their severity and penetrance across the population indicating that chronological ageing is distinct from biological age, likely due to both genetics and environment. Genetic syndromes and lifestyle can influence cellular biological ageing through increased DNA damage or decreased DNA repair. Defective DDR signalling drives genomic instability primarily via increased replication stress at common fragile sites, telomeres and the ribosomal rDNA repeats (rDNA), which due to their repetitive nature are difficult to replicate. Thus, a reduced ability to regulate rDNA is likely to lead to increased genomic instability. In addition to being difficult to replicate, the rDNA repeats are sensitive to exogenous DNA damage with the progressive loss of damaged repeats being proposed as a mechanism to maintain genomic stability. Loss of rDNA repeats in response to DNA damage is associated with decreased cellular fitness and ageing. Lifestyle exposure to agents that increase DNA replication stress (environment) or an inability to repair endogenous DNA lesions (genetic/epigenetic) may preferentially induce a reduction in rDNA repeats, which may be linked to biological ageing via decreasing cellular and tissue fitness. In general, the association of DNA damage associated rDNA loss with longevity is well-described in yeast models and this proposal aims to address the hypothesis that this mechanism similarly plays a role in mammalian ageing and cancer.