A UCP2 transgenic model for glucose metabolism and aging

描述(由申请人提供)：长期目标是设计药物干预措施，以调节线粒体解偶联功能，改善代谢稳态，延长寿命。我们感兴趣的是发展果蝇作为一个新的模型系统来研究线粒体解偶联调节影响能量存储/利用、葡萄糖稳态、胰岛素信号和衰老的机制。我们的初步结果表明，两个独立的线粒体解偶联蛋白hUCP2和mUCP1靶向果蝇胰岛素样肽产生细胞(IPC)，影响胰岛素样肽信息水平和葡萄糖稳态，并导致寿命延长。这项提议的目标是首先利用我们实验室实践良好的技术进行原则证明研究，以便更彻底地确定这些转基因果蝇的代谢特征。其次，我们将扩展我们对胰岛素信号通路组成部分的初步分析，以全面了解IPC中UCP表达增加可能如何影响胰岛素信号转导。第三，考虑到在这些果蝇中观察到的有希望的延长寿命的表型，我们将开发分子遗传学工具来允许在IPC中对UCP表达进行时间控制。通过分离成年期内皮祖细胞中UCP表达的影响，我们可以开始了解成体内皮祖细胞中UCP表达增加的系统性影响，不仅在代谢动态平衡方面，而且在衰老过程中。R21机制将为我们提供必要的资源来进行所提出的研究，并产生对全面开发新的果蝇模型至关重要的结果，以更充分地了解调制的线粒体解偶联在胰岛素信号转导和寿命中的作用。

DESCRIPTION (provided by applicant): The long-term objectives are to devise pharmacologic interventions to modulate mitochondrial uncoupling functions to improve metabolic homeostasis and extend life span. We are interested in developing Drosophila melanogaster as a novel model system for investigating the mechanisms whereby modulated mitochondrial uncoupling influences energy storage/utilization, glucose homeostasis, insulin signaling and aging. Our preliminary results demonstrate that targeting of two independent mitochondrial uncoupling proteins, hUCP2 and mUCP1, to the Drosophila insulin-like peptides producing cells (IPCs) affects the level of insulin-like peptide message, glucose homeostasis and leads to life span extension. The goals for this proposal are to first perform proof-of-principal studies with techniques well practiced in our lab in order to more thoroughly define the metabolic characteristics of these transgenic flies. Second, we will extend our preliminary analysis on components of the insulin signaling pathway to attain a comprehensive view of how increased UCP expression in the IPCs might be influencing insulin signaling. Third, given the promising life extension phenotype observed in these flies, we will develop molecular genetic tools to allow temporal control of UCP expression in the IPCs. By segregating the effect of UCP expression in IPCs during adulthood during development we can begin to understand the systemic impact of increased UCP expression in the adult IPCs, not only in metabolic homeostasis but also the aging process. The R21 mechanism would afford us the necessary resources to perform the proposed studies and yield results critical for a comprehensive development of a novel Drosophila model to more fully understand the role of modulated mitochondrial uncoupling in insulin signaling and longevity.