Cellular and Pathological Responses to Chromosome DNA Single-Strand Breaks

我的实验室专注于了解遗传物质(DNA)的断裂如何导致神经退化。这项拟议的工作将解决我目前的研究计划中出现的令人兴奋的新假说，涉及DNA单链断裂被感知和修复的机制/S，以及修复这些断裂的途径(单链断裂修复)令人兴奋和意想不到的新生理角色。我们还发现了一种未修复的单链断裂引发神经退化的机制，不仅为这一病理事件提供了第一个分子解释，而且为治疗干预开辟了可能的途径。我们计划在这里提出的新工作方案中追求这些新发现。虽然我们专注于罕见遗传疾病的实验模型来解决我们的科学问题，但这项工作的相关性可能会扩展到在正常老龄化人口中观察到的退行性疾病。这是因为单链断裂是细胞中最常见的DNA损伤，由氧化应激诱导；氧化应激是与衰老有关的病因因素。

My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to neurodegeneration. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning the mechanism/s by which DNA single-strand breaks are sensed and repaired, and exciting and unexpected novel physiological roles for the pathway that repairs these breaks (single-strand break repair). We have also uncovered a mechanism by which unrepaired single-strand breaks trigger neurodegeneration, providing not only the first molecular explanation of this pathological event but also opening up possible avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new Programme of work proposed here. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to degenerative diseases observed in the normal ageing population. This is because single-strand breaks are the commonest DNA lesions arising in cells and are induced by oxidative stress; an etiological factor implicated in ageing.