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.

抽象的：该项目的目的是测试核中遗传毒性应激的假设信号事件导致功能失调的线粒体积累，进而驱动细胞衰老和衰老。该假设得到了初步数据的支持 DNA修复核酸内切酶ERCC1-XPF的耗竭，导致小鼠导致氧化DNA损伤，过早细胞衰老和衰老的积累令人惊讶的是线粒体功能障碍并增加活性氧。而且， ERCC1缺乏秀丽隐杆线虫还显示了线粒体功能障碍的证据。 ERCC1- XPF仅用于修复核基因组，这表明核应激可以驱动线粒体异常。在鼠模型和共济失调的人类细胞和Hutchinson-gilford Progeria综合征。在这里我们建议定义核基因组不稳定性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。这这些研究的重要性是识别新型信号传导机制的可能性可以针对治疗的目标，以防止细胞衰老，衰老和与年龄有关的疾病由于细胞的随机损害而引起的。该方法将是全基因组的 ERCC-1 C.秀丽隐杆线虫中的RNAi屏幕，以鉴定抑制复合物1功能障碍的基因突变蠕虫。这种公正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和关于机制的新假设衰老。这将推动我过渡到成为独立调查员的过渡，第二次这个项目的重要目标。有针对性的初步屏幕确定了接近并揭示了几个对DNA损伤反应和线粒体至关重要的基因，包括ATM，P53，DRP1和PINK1，这些ATM在ERCC-1蠕虫中调节线粒体功能。在线虫中鉴定的细胞核和线粒体之间的这些新型联系将是在小鼠和鼠细胞中追求。利用两个的优势的创新方法非常强大的模型系统将允许识别新的分子靶标和支持将这种新知识的快速翻译成人类衰老。