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如何、何时以及在哪里优化线粒体解偶联，通过减少活性氧物种(ROS)的产生来最大限度地延长寿命。此外，还将探讨线粒体解偶联导致寿命延长的分子机制。作为这一应用的延伸，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，以及最终的寿命。考虑到现有的一些UCP基因敲除和转基因小鼠的可用性，这些研究是非常可行的，并可能揭示出这一点。这位候选人致力于将老龄化研究作为长期的职业目标。在康涅狄格州大学健康中心接受Stephen Helfand博士的培训，一位老龄领域的知名专家将使应聘者通过日常互动获得老龄研究的概念方法和必要技能，并有机会参加相关课程和研讨会，并定期向整个系提交研究结果，以进行严格审查。康涅狄格州大学老龄中心提供更多的智力资源，包括关于老龄的各种主题的研讨会。因此，同一系内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，使他们能够在衰老研究方面获得有针对性的培训，成为一名独立的、富有成效的研究人员。衰老的氧化应激假说认为，线粒体氧化代谢过程中产生的ROS主要导致氧化损伤的增加，这决定了衰老的速度。这一假说的预测是，减少氧化损伤的干预措施应该会减缓衰老速度，延长寿命。有人假设，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，我显示在成年果蝇神经元线粒体中表达人解偶联蛋白2可以延长平均寿命高达20%。在这项建议中，我将利用转基因方法在黑腹果蝇身上确定(I)在哪里以及何时必须增加解偶联才能延长寿命，(Ii)增加线粒体解偶联如何导致寿命延长，以及(Iii)增加线粒体解偶联的生理好处和成本是什么。

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.