Mechanisms of DNA Single-Strand Break-Induced Genetic Disease and Opportunities for Therapeutic Intervention

我的实验室专注于了解遗传物质(DNA)的断裂如何导致疾病。这项拟议的工作将解决在我目前的研究计划中出现的令人兴奋的新假说，该假说涉及S/未修复的DNA单链断裂(SSB)引发神经变性的机制。到目前为止，已发现6种人类遗传病的SSB修复存在缺陷；最新的一种是在我目前的MRC研究计划的主持下确定的(脊髓小脑性共济失调常染色体隐性26；SCAR26，其蛋白质XRCC1发生突变)。令人兴奋的是，我们已经发现了未经准备的SSB是如何引发这种疾病的，不仅为SSB如何致病提供了第一个分子解释，而且还为治疗干预开辟了可能的新途径。我们计划在这里提出的新研究计划中追求这些新发现。我们将使用分子、细胞和生理实验模型的组合来建立我们最近的发现，并在机制水平上定义SSB如何在体外和体内导致神经元功能缺陷，以及这些缺陷如何导致神经疾病。重要的是，我们还将继续向临床方向发展我们的工作，测试现有和新型药物/类药物分子恢复正常神经元功能和预防由SSB引起的神经疾病的能力。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更常见的退行性疾病，甚至扩展到正常老龄化人口。这是因为SSB是细胞中最常见的DNA损伤形式，不仅由氧化应激(氧化应激在大脑中升高，被认为有助于人类衰老)诱导，而且正如我们最近的工作中发现的那样，还由人类神经元调节其基因表达的正常过程诱导。

My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to disease. The proposed work will address exciting new hypotheses that have arisen during my current research programme concerning the mechanism/s by which unrepaired DNA single-strand breaks (SSBs), which are breaks in one strand of the DNA double helix, trigger neurodegeneration. To date, six human genetic diseases have been identified in which there is a defect in SSB repair; the latest one being identified under the auspices of my current MRC research programme (spinocerebellar ataxia autosomal recessive 26; SCAR26, which is mutated in the protein, XRCC1). Excitingly, we have discovered how unprepared SSBs trigger this disease, providing not only the first molecular explanation for how SSBs cause disease but also opening up possible new avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new research programme proposed here. We will employ a combination of molecular, cellular, and physiological experimental models to build on our recent discoveries and define at the mechanistic level how SSBs cause defects in neuronal function in vitro and in vivo, and how such defects lead to neurological disease. Importantly, we will also continue to develop our work in a clinical direction, by testing the ability of existing and novel drugs/drug-like molecules for their ability to restore normal neuron function and prevent neurological diseases that arise from SSBs. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to more common degenerative diseases and even to the normal ageing population. This is because SSBs are the commonest form of DNA damage arising in cells and are induced not only by oxidative stress (which is elevated in brain and is believed to contribute to human ageing) but as discovered in our recent work also by the normal processes by which human neurons regulate the expression of their genes.