Combining mammalian and Drosophila systems to study neuropsychiatric disorders

项目摘要： 该项目的总体目标是建立和追求一种创新的方法， 在哺乳动物系统中的发现研究，以及强大的 遗传模式生物黑腹果蝇作为一种新的策略，以确定和表征基因 以及在精神病发展过程中发生的行为变化的蛋白质。在 寻求新的医学疗法，特别是中枢神经系统疾病的治疗 涉及血清素的系统，如精神分裂症，精神病和抑郁症， 认识到识别单一生物靶标不太可能是成功的秘诀; 需要更广阔的视野。系统生物学就是这样一种方法，并且已经越来越多地 被认为是一个关键和动态的研究领域，因为它将特定的分子靶点放在一个 整体生化作用的背景。了解组件之间的复杂交互 在给定的生物系统内，导致输出的改变，例如行为的改变，可以 成为发现新疗法的重要途径。在这个框架内，我们的基础 一种假说认为，受异常血清素影响的分子事件，如基因表达变化， 大脑特定区域的受体激活，代表直接参与的分子，或 调节信号转导网络，这些网络是正常认知过程的基础， 导致神经精神紊乱。在这里，我们提出了一系列的实验后，系统的基础 方法来确定特定基因和蛋白质的功能和行为作用， 大鼠大脑前额叶皮层中特异性神经递质受体的药理学激活 一个关于精神病潜在的神经化学和遗传事件的动物模型， 精神分裂症我们将：1）确定额外的，也许更相关的，基因和蛋白质， 通过功能基因组学、蛋白质组学和基因组学研究大鼠前额叶皮层的特定区域 表达分析; 2）检查这些基因和蛋白质在行为中的功能作用， 果蝇的转译研究。我们坚信这 结合哺乳动物中枢神经系统药理学和整体 在我们强大的果蝇遗传模型中进行动物研究，是实现我们目标的最佳途径 目标.值得注意的是，我们的研究结果可能会导致新的治疗方法来治疗这种破坏性的疾病。 精神分裂症和精神病。

Project Abstract: The overall goals of this project are to establish and pursue an innovative approach combining discovery studies in mammalian systems with translational and functional studies in the powerful genetic model organism Drosophila melanogaster as a novel strategy to identify and characterize genes and proteins underlying the behavioral changes that occur during the development of psychosis. In the search for new medical therapies, and in particular treatments for disorders of the central nervous system involving serotonin, like schizophrenia, psychosis, and depression, there has been increasing recognition that identification of a single biological target is unlikely to be a recipe for success; a broader perspective is required. Systems biology is one such approach, and has been increasingly recognized as a crucial and dynamic area of research, as it places specific molecular targets within a context of overall biochemical action. Understanding the complex interactions between the components within a given biological system that lead to modifications in output, such as changes in behavior, may be important avenues of discovery to identify new therapies. Within this framework, our underlying hypothesis is that molecular events, such as gene expression changes, influenced by aberrant serotonin receptor activation in specific regions of the brain, represent molecules that directly participate in, or regulate signal transduction networks that underlie normal cognitive processes that when perturbed lead to neuropsychiatric disorders. Here, we propose a series of experiments following a systems based approach to determine the functional and behavioral role of specific genes and proteins that respond to pharmacological activation of specific neurotransmitter receptors in the prefrontal cortex of rat brain in a proposed animal model of the neurochemical and genetic events underlying psychosis and schizophrenia. We will: 1) Identify additional, and perhaps more relevant, genes and proteins in specific regions of the rat prefrontal cortex through functional genomic, proteomic, and gene expression analysis; 2) Examine the functional role of these genes and proteins in behaviors in translational studies in the fruit fly, Drosophila melanogaster. We strongly believe that this multidisciplinary systems-based approach combining mammalian CNS pharmacology and whole animal studies in our powerful genetic Drosophila model, is the best route to follow to achieve our goals. Significantly, our results may lead to novel avenues for therapeutics to treat such devastating diseases as schizophrenia and psychosis.