Coenzyme Q and Aging in Caenorhabditis elegans

描述：（由申请人提供）线虫秀丽隐杆线虫是一种 这是研究衰老过程的极好模型。突变 C.优雅线虫导致寿命延长，发育减慢 和迟钝的行为CLK-I是具有序列的线粒体多肽， 从人类到真菌的功能保护。的酵母同系物 CLK-I（Coq 7 p）对于泛醌（辅酶Q，或辅酶I）的生物合成是必需的。 CoQ）。线虫、大鼠和人类的COQ-1/COQ 7同源物都具有 恢复酵母coq 7无效突变体中的CoQ生物合成。我们最近的研究 梭秀丽线虫clk-l突变体表明衰老速率减慢， 发育和行为是由于辅酶Q生物合成中的生物化学缺陷。 在缺乏膳食辅酶Q的情况下，（通常通过以下食物提供给线虫： 辅酶Q丰富E. coli）clk-l突变体显示出其真正的表型-生长 发育早期停滞，发育后期不育。 本提案中提出的问题主要集中在CoQ 和衰老的关系。CoQ中缺陷的性质 将定义CLK-1突变体中的生物合成途径。这些研究将 利用代谢放射性标记和总脂质提取物分析， 辅酶Q和辅酶Q中间体。C. E. elegans E. coli-1突变体饲喂CoQ-充足的E.杆菌 依靠和吸收这种饮食辅酶Q。摄取的调节， 膳食辅酶Q的分布在任何系统中都不清楚。C. elegans 提供了一个外源辅酶Q在高等植物中同化代谢的模型 有机体在野生型线虫中存在类似的外源辅酶Q代谢。 日粮中添加辅酶Q对生长发育、成年行为的影响 和寿命将在野生型线虫中进行评估， 突变体C.优雅这些研究将确定clk-l 突变的生物合成辅酶Q的线虫系统;一个模型， 非常适合评估辅酶Q和衰老之间的关系。也是 这些研究可能会表明C. elegans可以提供一个 后生动物模型唯一适合解决有关Q摄取的问题， 代谢和分布。

DESCRIPTION: (provided by applicant) The nematode Caenorhabditis elegans is an excellent model for genetic studies of the aging process. Mutations in the clk-1 gene of C. elegans result in an extended life span, slowed development and sluggish behavior. CLK-l is a mitochondrial polypeptide with sequence and functional conservation from humans to fungi. The yeast homologue of CLK-l(Coq7p), is essential for the biosynthesis of ubiquinone (coenzyme Q, or CoQ). The nematode, rat and human homologs of clk-1/COQ7 all function to restore CoQ biosynthesis in the yeast coq7 null mutant. Our recent studies of the C. elegans clk-l mutants suggest that the slowed rates of aging, development and behavior are due to a biochemical defect in CoQ biosynthesis. In the absence of dietary CoQ, (normally provided to nematodes by a diet of CoQ-replete E. coli) the clk-l mutants display their true phenotype - growth arrest in early development and sterility when emerging from the dauer stage. The questions addressed in this proposal focus on the relationship between CoQ and aging in the nematode model. The nature of the defect in the CoQ biosynthetic pathway in the clk-l mutants will be defined. These studies will make use of metabolic radiolabeling and analysis of total lipid extracts for CoQ and CoQ-intermediates. C. elegans clk-1 mutants fed the CoQ-replete E. coli rely on and assimilate this dietary CoQ. The regulation of uptake and distribution of dietary CoQ is not understood in any system. C. elegans provides a model for the assimilation and metabolism of exogenous CoQ in higher organisms. A similar metabolism of exogenous CoQ exists in wild type nematodes. The effect of dietary CoQ supplementation on the development, adult behavior and life span will be evaluated in wild type nematodes, and in other cog mutants of C. elegans. These studies will determine the effect of the clk-l mutations on the biosynthesis of CoQ in the nematode system; a model that is ideal for evaluating the relationship between coenzyme Q and aging. It is also likely that these studies will indicate whether C. elegans can provide a metazoan model uniquely suited to address questions regarding Q uptake, metabolism and distribution.