Role of the DNA damage signalling and repair pathways in the prevention of tumorigenesis and neurodegeneration in the central nervous system

DNA损伤信号传导和修复途径在预防中枢神经系统肿瘤发生和神经变性中的作用

• 批准号: 60208195
• 负责人: Dr. Pierre-Olivier Frappart, Ph.D.
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/60208195?language=en
• 关键词: Role; DNA; damage; signalling; repair

The integrity of DNA inside cells is constantly being challenged by endogenous and exogenous DNA-damaging agents. Stability of genomic DNA organization is fundamental to the faithful transmission of genetic information and the prevention of carcinogenesis. The developing nervous system exhibits a high sensitivity to DNA damage and in particularly to DNA double-strand breaks (DSBs). In nervous system, DNA DSBs trigger a cascade of signalling events that lead to repair and resolution of the break, or as is very frequent, apoptosis. Additionally the importance of DSBs repair to the central nervous system (CNS) is illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DSBs repair such as A-T, A-TLD and NBS or Seckel syndrome. The objectives of this research project is to analyse the consequences of inactivation of DNA damage repair/signalling genes on the normal development and neurodegeneration of the central nervous system using mouse models. The research project will be focused on two genes SMC1 (coding for a DNA damage signalling protein) and RINT-1 (coding for a Rad50 interacting protein) that are involved in DNA damage response. This study will allow to acquire a better knowledge about the response of CNS to DNA damage. Ultimately, it will provide new clues to elaborate treatments for brain tumours and neurodegenerative diseases.

细胞内DNA的完整性不断受到内源性和外源性DNA损伤剂的挑战。基因组DNA组织的稳定性是遗传信息可靠传递和预防癌症发生的基础。发育中的神经系统对DNA损伤，特别是DNA双链断裂（DSB）表现出高度敏感性。在神经系统中，DNA双链断裂引发一系列信号传导事件，导致断裂的修复和解决，或者非常常见的是，细胞凋亡。此外，DSB修复对中枢神经系统（CNS）的重要性通过在患有与DSB修复缺陷相关的遗传性疾病的患者中观察到的神经异常来说明，所述遗传性疾病例如A-T、A-BSB和NBS或Seckel综合征。本研究项目的目的是使用小鼠模型分析DNA损伤修复/信号传导基因失活对中枢神经系统正常发育和神经退行性变的后果。该研究项目将集中在两个基因SMC 1（编码DNA损伤信号蛋白）和RINT-1（编码Rad 50相互作用蛋白），它们参与DNA损伤反应。本研究将有助于更好地了解CNS对DNA损伤的反应。最终，它将为脑肿瘤和神经退行性疾病的精心治疗提供新的线索。