Putative Drosophila Uncoupling Proteins and Aging

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、何时和何地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，负责的线粒体解偶联介导的寿命延长的分子机制将进行调查。作为本申请的扩展，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，以及最终的寿命。这些研究是可行的，并可能揭示了现有的UCP敲除和转基因小鼠的数量。候选人致力于老龄化研究作为一个长期的职业目标。Stephen Helfand博士在康州大学健康中心的培训，老龄化领域的知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的机会，获得老龄化研究的概念方法和必要技能，并定期在整个部门进行严格审查之前展示研究结果。康州大学老龄化中心提供进一步的智力资源，包括关于老龄化的各种主题的研讨会。因此，同一部门内的两个额外的果蝇实验室为候选人提供了一个智力刺激的环境，以获得衰老研究的相关培训，成为一个独立的，富有成效的调查员。衰老的氧化应激假说指出，主要由线粒体中氧化代谢过程中产生的ROS引起的氧化损伤的累积速率决定了衰老的速率。这一假说的预测是，减少氧化损伤的干预措施应该减缓衰老速度并延长寿命。据推测，线粒体解偶联的增加降低了线粒体ROS的产生和氧化损伤。在本提案的初步结果部分，我表明，成人果蝇神经元线粒体中的人类解偶联蛋白2的表达延长平均寿命高达20%。在这个建议中，我将利用转基因方法在果蝇，以确定（i）在何处和何时解偶联必须增加延长寿命，（ii）如何增加线粒体解偶联可能会导致寿命延长，（iii）增加线粒体解偶联的生理利益和成本是什么。

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.