Mitochondrial Genetics of Aging in Drosophila

果蝇衰老的线粒体遗传学

基本信息

批准号：
8520128
负责人：
DAVID M RAND
金额：
$ 29.19万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-08-31
项目状态：
已结题

项目摘要

Project Summary A primary cause of aging is thought to be reactive oxygen species (ROS) produced in mitochondria as byproducts of oxidative phosphorylation (OXPHOS). Manipulations that either increase ROS scavenging or decrease ROS production have extended longevity in some, but not all systems. Caloric or dietary restriction (CR or DR) remains the single most repeatable intervention that extends longevity in all organisms studied to date. Recent studies have identified a relationship between CR or DR, altered mitochondrial function, and extended longevity. In this proposal we present clear evidence that mtDNA haplotypes 1) can extend or shorten longevity, 2) modify the longevity-extending effects of diet restriction, 3) modify the longevity-extending effects of the insulin receptor substrate mutation chico1. These findings provide proof of principle that nuclear-mtDNA epistasis mapping is effective in uncovering genetic mechanisms of longevity extension by diet restriction. The results lead to the hypothesis that genes encoded in mtDNA are critical for the nutrient-dependent modification of longevity. We will exploit these mtDNA replacement strains to test this hypothesis using epistasis experiments with the Rpd3 - Sir2 and TOR pathways that play important roles in nutrient-based changes in longevity. These genetic constructs will also be used to test the general hypothesis that mtDNA genotype modifies longevity through changes in the level of oxidative damage. There are three specific aims that will test each of these hypotheses: 1) Does mtDNA genotype alter the Rpd3-dependent extension of longevity? We will test the hypothesis that mitochondrial genes modify the effect of Rpd3 on longevity, and Rpd3's independence from DR. 2) Does mtDNA genotype alter the Sir2-dependent effects of dietary restriction? We will test the hypothesis that mtDNA genotype modifies the role Sir2 plays in regulating the response to DR by pairing mtDNAs with over-expression and tissue specific expression constructs on different diets. 3) Does mtDNA genotype modify the TOR pathway effects on nutrient sensing and longevity extension? We will test the hypothesis that mtDNA genotype modifies the role that TOR and Tsc2 play in extending longevity by pairing mtDNAs with hypomorphic and tissue specific expression constructs of these genes.

项目摘要衰老的主要原因被认为是线粒体中产生的活性氧（ROS）作为氧化磷酸化（OXPHOS）的副产物。增加ROS的操作在某些系统中，清除或减少ROS的产量已延长了寿命。热量或饮食限制（CR或DR）仍然是最可重复的干预措施迄今为止研究的所有生物中延长寿命。最近的研究已经确定了一种关系在CR或DR之间，线粒体功能改变和延长寿命。在这个建议中，我们目前的明确证据表明mtDNA单倍型1）可以延长或缩短寿命，2）修改饮食限制的寿命延伸影响，3）修改胰岛素的寿命延伸效果受体底物突变Chico1。这些发现提供了原理证明了核麦芽岩上静脉映射可有效地发现饮食延长寿命的遗传机制限制。结果导致了以下假设：mtDNA中编码的基因对于养分依赖寿命的修饰。我们将利用这些mtDNA替换菌株使用rpd3 -siR2和播放的tor途径的上位实验检验这一假设在基于营养的寿命变化中的重要作用。这些遗传结构也将被使用为了检验一般假设，即mtDNA基因型通过变化改变了寿命氧化损伤水平。有三个具体目标将测试这些假设中的每一个： 1）mtDNA基因型是否改变了寿命的rpd3依赖性扩展？我们将测试线粒体基因修改RPD3对寿命的影响和RPD3的影响的假设独立于博士。 2）mtDNA基因型会改变饮食的siR2依赖性作用吗限制？我们将检验以下假设，即mtDNA基因型修改了SiR2在通过将MTDNA与过表达和特定于组织配对来调节对DR的反应表达构造在不同的饮食上。 3）mtDNA基因型是否修改了TOR途径对营养感应和寿命扩展的影响？我们将测试mtDNA的假设基因型通过将mtdnas与这些基因的型和组织特异性表达构建体。