Putative Drosophila Uncoupling Proteins and Aging

假定的果蝇解偶联蛋白与衰老

• 批准号: 7059327
• 负责人: YIH-WOEI Chiu FRIDELL
• 金额: $ 2.16万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059327
• 关键词: DNA damage; Drosophilidae; adenosine triphosphate; aerobiosis; aging; body composition; body physical activity; body weight; cell biology; free radical oxygen; gene expression; genetically modified animals; lipids; longevity; membrane transport proteins; metabolism; mitochondria; oxidative stress; stress

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优化的线粒体解偶联如何、何时以及在何处可以通过减少活性氧（ROS）的产生来最大限度地延长寿命。此外，还将研究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 积累、氧化损伤、解偶联蛋白与其他 ROS 解毒酶之间的相互作用，并最终，寿命。这些研究很容易实现，并且鉴于大量现有的 UCP 敲除和转基因小鼠的可用性，可能会有所启示。候选人致力于衰老研究作为长期职业目标。与康涅狄格大学健康中心衰老领域知名专家Stephen Helfand博士一起接受培训，将使候选人通过日常互动以及参加相关课程、研讨会和演讲的机会，获得衰老研究的概念方法和必要技能研究结果定期在整个部门进行严格审查。康涅狄格大学老龄化中心提供更多智力资源，包括有关老龄化各种主题的研讨会。因此，同一系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，让他们获得衰老研究的相关培训，成为一名独立、富有成效的研究者。衰老的氧化应激假说指出，氧化损伤的累积速率（主要由线粒体氧化代谢过程中产生的ROS产生）决定了衰老速率。这一假设的预测是，减少氧化损伤的干预措施应该会减缓衰老速度并延长寿命。据推测，线粒体解偶联的增加会减少线粒体 ROS 的产生和氧化损伤。在当前提案的初步结果部分中，我表明，成年果蝇神经元线粒体中人类解偶联蛋白 2 的表达可将平均寿命延长高达 20%。在本提案中，我将利用黑腹果蝇的转基因方法来确定（i）必须在何时何地增加解偶联以延长寿命，（ii）增加线粒体解偶联如何导致寿命延长，以及（iii）什么是增加线粒体解偶联的生理益处和成本。