Effect of parkin on DNA damage induced rearrangements

Parkin 对 DNA 损伤诱导重排的影响

• 批准号: 6965251
• 负责人: ROBERT H SCHIESTL
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-16 至 2007-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965251
• 关键词: DNA damage; Parkinson' s disease; cancer risk; carcinogens; environmental exposure; gene deletion mutation; gene environment interaction; gene expression; gene frequency; genetic recombination; genetic susceptibility; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; parkin gene /protein; smoking; tobacco abuse

DESCRIPTION (provided by applicant): The frequency of cancer overall and of cigarette smoke induced cancer specifically is reduced in Parkinson's Disease (PD) patients. This reduced cancer frequency is more pronounced among early onset PD patients that are more likely due to genetic predisposition. Nothing is known about the underlying biological mechanism. Mutations in parkin predispose people to PD. Mice with a knockout mutation in the parkin gene have been generated and they show behavioral deficits similar to PD patients. This application is to determine whether the effect on the frequency of genetic instability of environmental cancer causing factors can be reduced in mice lacking parkin. We have previously shown that DNA deletion events in vivo are increased by environmental as well as genetic cancer predisposing factors. The deletion assay is based on the quantification of black spots on fur and eyes resulting from reversion of the pun mutation. This reversion occurs by recombination between two copies of an internal 70 kb repeat within the p gene leading to deletion of one copy. In preliminary results we showed that a variety of carcinogens including benzo(a)pyrene, benzene and cigarette smoke induce DNA deletions in mice. We hypothesize for aim 1 that such induction of DNA deletions by environmental carcinogens may be reduced in mice lacking parkin. In addition, we propose to determine cigarette smoke induced levels of nicotine and cotinine, DNA adducts, oxidative DNA lesions, glutathione and antioxidant vitamins to correlate such levels with the levels of smoke induced DNA deletions and to possibly gain molecular insights into any possible effect of parkin thereon. If our hypothesis turns out to be true, one could use these mice as model systems to further study the mechanistic basis of the interaction of lack of parkin with DNA repair and cancer.

描述（由申请人提供）：帕金森病（PD）患者的总体癌症频率和香烟烟雾诱导的癌症频率降低。这种癌症频率的降低在早发性PD患者中更为明显，这些患者更有可能是由于遗传易感性。我们对潜在的生物学机制一无所知。parkin基因的突变使人们容易患PD。已经产生了在parkin基因中具有敲除突变的小鼠，它们表现出与PD患者相似的行为缺陷。本申请旨在确定是否可以在缺乏parkin的小鼠中降低环境致癌因素对遗传不稳定性频率的影响。我们以前已经表明，DNA缺失事件在体内增加了环境以及遗传癌症易感因素。缺失试验基于对由pun突变回复引起的皮毛和眼睛上的黑点的定量。这种逆转通过p基因内的内部70 kb重复的两个拷贝之间的重组发生，导致一个拷贝的缺失。在初步结果中，我们发现，多种致癌物，包括苯并（a）芘，苯和香烟烟雾诱导小鼠DNA缺失。我们假设目标1，这种诱导的DNA缺失的环境致癌物质可能会减少在小鼠缺乏parkin。此外，我们建议确定香烟烟雾诱导的尼古丁和可替宁、DNA加合物、氧化DNA损伤、谷胱甘肽和抗氧化维生素的水平，以将这些水平与烟雾诱导的DNA缺失水平相关联，并可能获得对帕金对其任何可能影响的分子见解。如果我们的假设被证明是正确的，人们可以使用这些小鼠作为模型系统，以进一步研究缺乏parkin与DNA修复和癌症相互作用的机制基础。