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Modulators of DNA damage associated nucleo-mitochondrial communication in aging

衰老过程中与核线粒体通讯相关的 DNA 损伤调节剂

基本信息

批准号：
9922460
负责人：
Aditi U Gurkar
金额：
$ 8.79万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-12-31
项目状态：
已结题

项目摘要

Abstract: The goal of this project is to test the hypothesis that genotoxic stress in the nucleus triggers signaling events that result in accumulation of dysfunctional mitochondria, which in turn drives cellular senescence and aging. The hypothesis is supported by preliminary data demonstrating that depletion of the DNA repair endonuclease ERCC1-XPF in cells and mice causes accumulation of oxidative DNA damage, premature cellular senescence and aging, but also surprisingly mitochondrial dysfunction and increased reactive oxygen species. Moreover, ERCC1-deficient C. elegans also show evidence of mitochondrial dysfunction. ERCC1- XPF is required only for the repair of the nuclear genome, suggesting that nuclear stress can drive mitochondrial abnormalities. Similar observations have been made in murine models and human cells of ataxia telangiectasia and Hutchinson-Gilford Progeria syndrome. Herein we propose to define the molecular mechanism(s) by which nuclear genomic instability triggers mitochondrial dysfunction using an innovative combination of powerful genetic tools. The significance of these studies is the possibility of identifying novel signaling mechanisms that could be targeted therapeutically to prevent cell senescence, aging and age-related diseases arising as a consequence of stochastic damage to cells. The approach will be a genome-wide RNAi screen in ercc-1 C. elegans to identify genes that suppress Complex 1 dysfunction in mutant worms. This unbiased approach will yield pathways that impact mitochondrial function in response to endogenous genotoxic stress and undoubtedly new hypotheses about mechanisms of aging. This will fuel my transition to becoming an independent investigator, a second important goal of this project. A targeted preliminary screen established the feasibility of the approach and revealed several genes critical for the DNA damage response and mitophagy, including ATM, p53, DRP1 and PINK1,that regulate mitochondrial function in ercc-1 worms. These novel links between the nucleus and mitochondria identified in nematodes will be pursued in mice and murine cells. The innovative approach of exploiting the strengths of two very powerful model systems will allow identification of novel molecular targets and support rapid translation of this new knowledge to human aging.

摘要：这个项目的目标是检验细胞核中的遗传毒性应激引发信号事件，导致功能障碍的线粒体的积累，这反过来又驱动细胞衰老和老化。初步数据支持这一假设，细胞和小鼠中DNA修复核酸内切酶ERCC 1-XPF的缺失导致氧化性DNA损伤的积累，过早的细胞衰老和老化，而且令人惊讶的是线粒体功能障碍和活性氧增加。此外，委员会认为， ERCC 1缺陷型C.秀丽线虫也显示出线粒体功能障碍的证据。ERCC1- XPF仅用于修复核基因组，这表明核应激可以导致线粒体异常在鼠模型中也进行了类似的观察，共济失调毛细血管扩张症和哈钦森-吉尔福德早衰症的人类细胞。在此我们建议定义核基因组不稳定性触发的分子机制线粒体功能障碍，使用强大的遗传工具的创新组合。的这些研究的重要性在于有可能鉴定新的信号传导机制，可以有针对性地治疗，以防止细胞衰老，衰老和与年龄有关的疾病由于细胞随机损伤而产生。该方法将是全基因组的 ercc-1C中RNAi的筛选elegans鉴定抑制复合物1功能障碍的基因，变异蠕虫这种无偏见的方法将产生影响线粒体功能的途径，对内源性遗传毒性应激的反应，无疑是关于机制的新假说衰老的迹象这将推动我成为一名独立调查员，这个项目的重要目标。有针对性的初步筛选确定了方法并揭示了几个对DNA损伤反应和线粒体自噬至关重要的基因，包括ATM、p53、DRP 1和PINK 1，它们在ercc-1蠕虫中调节线粒体功能。这些在线虫中发现的细胞核和线粒体之间的新联系将是在小鼠和鼠细胞中进行。创新的方法，利用两个优势，非常强大的模型系统将允许识别新的分子靶点和支持将这些新知识迅速转化为人类衰老的知识。