Targeting DNA G4 to investigate ageing biology

G-四链体是可以在人类基因组和转录组中形成的DNA和RNA二级结构。在过去的十年中，已经开发了小分子和化学生物学工具来探测细胞中的G-四链体结构，但大多数这种策略提供了这些结构的稳定化，而不是它们的展开。通过化学-生物学方法诱导G-四链体解折叠对于罕见遗传疾病如Cockayne综合征和ALS的治疗干预具有巨大潜力，这两种疾病都是由G-四链体结构的不受控制的细胞积累引起的。Souro的项目重点是研究短的化学修饰的反义寡核苷酸的应用，以实现G-四链体的不稳定和展开。虽然，他的主要项目是集中在如何反义靶向方法可以用来实现G-四链体结构的热力学和动力学不稳定的基本生物物理学的理解，在这个博士项目期间产生的知识将是高度相关的调查的潜力反义策略治疗ALS和Cockayne综合征通过G-四链体不稳定。

G-quadruplexes are DNA and RNA secondary structures that can form in the human genome and transcriptome. Small-molecules and chemical-biology tools to probe G-quadruplexes structures in cells have been developed over the past decade, but most of this strategies provide a stabilisation of these structure rather than their unfolding. Inducing G-quadruplex unfolding by means of chemical-biology approaches has great potential for therapeutic intervention towards rare genetic diseases like Cockayne Syndrome and ALS, which are both caused by an uncontrolled cellular accumulation of G-quadruplex structures. Souro's project is focused on investigating the application of short chemically-modified antisense oligonucleotides to achieve G-quadruplex destabilisation and unfolding. Although, his main project is focused on the fundamental biophysical understanding of how antisense-targeting approaches can be used to achieve thermodynamic and kinetic destabilisation of G-quadruplex structures, the knowledge generated during this PhD project will be of high relevance to investigate the potential of antisense strategies to treat ALS and Cockayne Syndrome by means of G-quadruplex destabilisation.