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来调节线粒体解偶联功能，以改善代谢稳态和延长寿命。我们有兴趣发展黑腹果蝇作为一个新的模型系统，研究线粒体解偶联调节影响能量储存/利用、葡萄糖稳态、胰岛素信号传导和衰老的机制。我们的初步研究结果表明，将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（IPCs），影响胰岛素样肽信息水平、葡萄糖稳态并导致寿命延长。本提案的目标是首先使用我们实验室实践的技术进行原理验证研究，以便更彻底地定义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成分的初步分析，以全面了解IPCs中UCP表达增加如何影响胰岛素信号通路。第三，鉴于在这些果蝇中观察到的有希望的延长寿命表型，我们将开发分子遗传学工具，以允许在IPCs中对UCP表达进行时间控制。通过分离成年期IPCs中UCP表达的影响，我们可以开始理解成年期IPCs中UCP表达增加的系统性影响，不仅在代谢稳态中，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拟议的研究，并为全面开发新的果蝇模型提供关键的结果，以更充分地了解调节线粒体解偶联在胰岛素信号传导和寿命中的作用。

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.