A UCP2 transgenic model for glucose metabolism and aging

描述（由申请方提供）：长期目标是设计药理学干预措施来调节线粒体解偶联功能，以改善代谢稳态并延长寿命。我们有兴趣开发果蝇作为一种新的模型系统，用于研究调节线粒体解偶联影响能量储存/利用，葡萄糖稳态，胰岛素信号和衰老的机制。我们的初步研究结果表明，两个独立的线粒体解偶联蛋白，hUCP 2和mUCP 1，靶向果蝇胰岛素样肽产生细胞（IPC）影响胰岛素样肽的信息，葡萄糖稳态的水平，并导致寿命延长。该提案的目标是首先使用我们实验室中实践良好的技术进行主要验证研究，以便更彻底地定义这些转基因果蝇的代谢特征。第二，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表达的增加如何影响胰岛素信号传导。第三，鉴于在这些果蝇中观察到的有希望的寿命延长表型，我们将开发分子遗传工具，以允许在IPC中暂时控制UCP表达。通过分离UCP表达在成年期发育过程中的作用，我们可以开始了解UCP表达增加在成年IPC中的全身影响，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，并产生对全面开发一种新的果蝇模型至关重要的结果，以更充分地了解调制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.