A UCP2 transgenic model for glucose metabolism and aging

葡萄糖代谢和衰老的 UCP2 转基因模型

• 批准号: 7514721
• 负责人: YIH-WOEI Chiu FRIDELL
• 金额: $ 13.96万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7514721
• 关键词: Adult; Affect; Age; Aging; Aging-Related Process; Attenuated; Beta Cell; Biological; Biological Models; Cells; Characteristics; Condition; Data; Development; Drosophila genus; Drosophila melanogaster; Exploratory/Developmental Grant; Fasting; Fertility; Gene Expression; Glucose; Goals; Growth and Development function; Hemolymph; Homeostasis; Human; Hyperglycemia; Insulin; Insulin Signaling Pathway; Intervention; Life Extension; Longevity; Measures; Metabolic; Mitochondria; Modeling; Molecular Genetics; Mouse Protein; Mus; Nervous system structure; Neurons; Nuclear Translocation; Nutrient; Peptides; Phenotype; Physical activity; Physiological; Physiology; Rate; Reading; Research; Resistance; Resources; Role; Starvation; Stress; System; Techniques; Time; Tissues; Transcript; Transgenic Model; Transgenic Organisms; UCP2 protein; blood glucose regulation; feeding; fly; gene therapy; glucose metabolism; improved; insulin signaling; interest; mature animal; mitochondrial uncoupling protein; novel; promoter; sugar; tool

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.

描述（由申请人提供）：长期目标是设计药理学干预措施以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Melanogaster作为一种新型模型系统，用于调查线粒体解偶联的机制，从而影响了储能/利用，葡萄糖稳态，胰岛素信号传导和衰老。我们的初步结果表明，靶向两个独立的线粒体解偶联蛋白HUCP2和MUCP1靶向果蝇胰岛素样产生的细胞（IPC）会影响胰岛素样肽信息，葡萄糖稳态，并导致寿命延伸。该提案的目标是首先通过实验室实践的技术首先进行主要研究证明，以便更彻底地定义这些转基因苍蝇的代谢特征。其次，我们将扩展对胰岛素信号通路的组件的初步分析，以便全面了解IPC中UCP表达如何影响胰岛素信号传导。第三，鉴于在这些苍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，以允许对IPC中UCP表达的时间控制。通过隔离开发过程中成年期UCP表达在IPC中的影响，我们可以开始了解成人IPC中UCP表达增加的系统影响，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执行拟议的研究，并产生对新型果蝇模型的全面发展至关重要的结果，以更充分地了解调制线粒体解偶联在胰岛素信号和寿命中的作用。