Drosophila as a model genetic system to study neuropsychiatric disorders

描述(申请人提供)：这个项目的目标是开发果蝇，作为一个遗传上容易处理的模型系统，以研究人类神经精神疾病的分子机制，这些疾病涉及血清素，如精神分裂症和抑郁症。我们建议用产生可观察到的行为效应的特定的5-羟色胺能精神分裂药物来治疗苍蝇。正如大多数以前研究的通路所显示的那样，将5-羟色胺受体相互作用与行为联系起来的分子事件在苍蝇和人类之间可能是高度保守的。利用苍蝇研究这些保守的神经化学事件，发挥了极其强大的基因技术，以快速阐明关键途径和分子，否则可能需要数年时间，成本大大增加，通过传统的哺乳动物方法来识别。重要的是，苍蝇被认为表达哺乳动物5-HT2受体的功能同源基因，以及哺乳动物5-HT1a、5-HT7、多巴胺D1和D2、GABA、NMDA和代谢性谷氨酸受体的同源基因，所有这些都与多种人类神经精神疾病密切相关。在这里，我们建议利用分子、遗传和行为实验来研究果蝇中枢5-羟色胺系统的行为、2)回路和3)神经药理学，为未来的研究奠定坚实的基础。这些果蝇研究与正在进行的哺乳动物靶标识别实验相结合，形成了一种新的基于系统的方法来探索与人类神经精神障碍相关的神经化学事件，并将对促进发现新的治疗靶点具有重要意义。关于公共卫生：精神分裂症是一种衰弱的神经精神疾病，大约每100个美国人中就有一个人受到影响，每年给美国经济造成近630亿美元的损失。迫切需要新的方法来了解潜在的精神分裂症机制，以便进一步了解和治疗这种疾病以及其他精神障碍。我们建议开发果蝇作为研究这些疾病潜在的5-羟色胺神经化学的模型系统。这一模型系统的开发和使用将提高治疗这些疾病的治疗新靶点的发现率。

DESCRIPTION (provided by applicant): The goal of this project is to develop the fruit fly, Drosophila melanogaster, as a genetically tractable model system to investigate molecular mechanisms underlying human neuropsychiatric disorders that involve serotonin, such as schizophrenia and depression. We propose to treat flies with specific serotonergic psychotomimetic agents that produce an observable behavioral effect. As shown with most previously studied pathways, the molecular events linking serotonin receptor interactions to behavior are likely to be highly conserved between the fly and humans. The use of the fly to study these conserved neurochemical events brings into play extremely powerful genetic techniques to rapidly elucidate key pathways and molecules that otherwise could take years, at a substantially greater cost, to identify by traditional mammalian-based methods. Importantly, the fly is believed to express a functional ortholog of the mammalian 5-HT2 receptor, as well as orthologs of the mammalian 5-HT1A, 5-HT7, dopamine D1 and D2, GABA, NMDA, and metabotropic glutamate receptors, all of which have been strongly implicated in a variety of human neuropsychiatric disorders. Here, we propose investigations to characterize the: 1) behaviors, 2) circuitry, and 3) neuropharmacology of the Drosophila CNS serotonin system using molecular, genetic, and behavioral experiments to create a solid foundation for future research. These Drosophila studies, in combination with ongoing proposed mammalian target identification experiments, together form a novel systems-based approach to explore neurochemical events relevant to neuropsychiatric disorders in humans, and will be of great importance to facilitate the discovery of novel targets for therapeutics. Summary with respect to public health: Schizophrenia is a debilitating neuropsychiatric disorder that affects about one out of every 100 Americans at a cost to the U.S. economy of nearly $63 billion/year. New approaches towards understanding underlying schizophrenia mechanisms are urgently needed in order to further understand and treat this disease, as well as other psychiatric disorders. We propose to develop the fruit fly as a model system to study the underlying serotonin neurochemistry of these diseases. The development and utilization of this model system will lead to an enhanced discovery rate of novel targets for therapeutics to treat these conditions.