Putative Drosophila Uncoupling Proteins and Aging

假定的果蝇解偶联蛋白与衰老

基本信息

批准号：
7257509
负责人：
YIH-WOEI Chiu FRIDELL
金额：
$ 8.1万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term objectives of this application are to determine how, when, and where optimized mitochondrial uncoupling could maximally extend life span through reduction of reactive oxygen species (ROS) production. In addition, the molecular mechanisms responsible for the life span extension mediated by mitochondrial uncoupling will be investigated. As an extension of this application, the impact of mitochondrial uncoupling on aging will be examined in mammalian models to further assess the cellular consequences including age-related ROS accumulation, oxidative damage, the interplay between the uncoupling protein and other ROS detoxifying enzymes, and ultimately, life span. These studies are readily feasible and could be revealing given the availability of a number of existing UCP knock out and transgenic mice. The candidate is committed to aging research as a long-term career goal. Training with Dr. Stephen Helfand at the UConn Health Center, a well-known expert in the aging field will allow the candidate to acquire both conceptual approaches and necessary skills for aging research through daily interactions and the opportunities in attending relevant courses and seminars and presenting research results regularly before the entire department for critical review. The UConn Center on Aging offers further intellectual resources including seminars on various topics on aging. Two additional Drosophila laboratories within the same department thus offer an intellectually stimulating environment for the candidate to attain pertinent training in aging research to become an independent, productive investigator. The oxidative stress hypothesis of aging states that the rate of accrual of oxidative damage, resulting primarily from ROS generated during oxidative metabolism in mitochondria, determines the rate of aging. A prediction of this hypothesis is that interventions that reduce oxidative damage should slow the rate of aging and extend life span. It has been hypothesized that an increase in mitochondrial uncoupling decreases mitochondrial ROS production and oxidative damage. In the preliminary results section of the current proposal I show that expression of human uncoupling protein 2 in the mitochondria of adult Drosophila melanogaster neurons extends mean life span by up to 20%. In this proposal, I will make use of transgenic approaches in Drosophila melanogaster to determine (i) where and when uncoupling must be increased to extend life span, (ii) how increased mitochondrial uncoupling may cause life span extension, and (iii) what are the physiological benefits and costs of increased mitochondrial uncoupling.

描述（由申请人提供）：本申请的长期目标是确定如何，何时和何处通过降低活性氧（ROS）产生来最大程度地延长寿命。此外，将研究负责通过线粒体解偶联介导的寿命延长的分子机制。作为该应用的扩展，将在哺乳动物模型中检查线粒体解偶联对衰老的影响，以进一步评估细胞后果，包括与年龄相关的ROS累积，氧化损伤，氧化性损伤，脱偶联蛋白和其他ROS ROS排毒酶之间的相互作用，以及最终的相互作用，寿命。这些研究很容易可行，并且鉴于许多现有的UCP淘汰和转基因小鼠的可用性可能会揭示。候选人致力于将老化研究作为长期职业目标。在UConn Health Center的Stephen Helfand博士的培训，老龄化领域的著名专家将使候选人通过日常互动以及参加相关课程和研讨会和介绍的机会来获得概念方法和老化研究的必要技能定期在整个部门之前进行研究结果进行批判性审查。 UConn老龄化中心提供了进一步的智力资源，包括有关衰老的各种主题的研讨会。因此，同一部门内的另外两个果蝇实验室为候选人提供了一个智力刺激的环境，以便在老龄化研究中获得相关的培训，以成为独立的生产研究人员。衰老的氧化应激假说指出，主要是由线粒体中氧化代谢过程中产生的ROS产生的氧化损伤的速率决定了衰老率。对此假设的预测是，减少氧化损伤的干预措施应减缓衰老率并延长寿命。假设线粒体解偶联的增加会降低线粒体ROS的产生和氧化损伤。在当前提案的初步结果部分中，I表明，成年果蝇果蝇神经元的线粒体中人解偶联蛋白2的表达将平均寿命延长高达20％。在此提案中，我将利用果蝇中的转基因方法来确定（i）必须增加何时和何时增加寿命以延长寿命，（ii）线粒体解偶联的增加可能会导致寿命延长，以及（iii）什么是（iii）什么是线粒体解偶联增加的生理益处和成本。