Drosophila as a model genetic system to study neuropsychiatric disorders

果蝇作为研究神经精神疾病的模型遗传系统

• 批准号: 7488633
• 负责人: CHARLES D NICHOLS
• 金额: $ 3.31万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488633
• 关键词: Animal Model; Antipsychotic Agents; Behavior; Behavioral; Biological Models; Development; Disease; Drosophila genus; Drosophila melanogaster; Etiology; Event; Genetic; Genetic Models; Genetic Techniques; Goals; Human; Link; Molecular; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Principal Investigator; Process; Range; Receptor Activation; Research; Serotonin; Serotonin Agents; System; Therapeutic; fly; neurochemistry; neuropsychiatry; programs; response; serotonin receptor; tool

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.

描述（由申请人提供）：本项目的目标是开发果蝇（Drosophila melanogaster）作为遗传学上易于处理的模型系统，以研究涉及血清素的人类神经精神疾病（如精神分裂症和抑郁症）的分子机制。 我们建议用特定的能产生可观察到的行为效应的拟精神病药物治疗苍蝇。 正如大多数先前研究的途径所示，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。 使用苍蝇来研究这些保守的神经化学事件，可以发挥极其强大的遗传技术的作用，快速阐明关键途径和分子，否则通过传统的哺乳动物方法可能需要数年时间才能识别这些关键途径和分子，而且成本要高得多。 重要的是，果蝇被认为表达哺乳动物5-HT 2受体的功能性直系同源物，以及哺乳动物5-HT 1A、5-HT 7、多巴胺D1和D2、GABA、NMDA和代谢型谷氨酸受体的直系同源物，所有这些都与多种人类神经精神障碍密切相关。 在这里，我们提出调查的特点：1）行为，2）电路，和3）神经药理学的果蝇中枢神经系统的血清素系统使用分子，遗传和行为实验，为未来的研究奠定了坚实的基础。 这些果蝇的研究，结合正在进行的哺乳动物目标识别实验，共同形成了一种新的基于系统的方法来探索与人类神经精神疾病相关的神经化学事件，并将非常重要，以促进新的治疗靶点的发现。 精神分裂症是一种使人衰弱的神经精神障碍，每100个美国人中就有一个受到影响，美国经济每年损失近630亿美元。 为了进一步了解和治疗这种疾病以及其他精神疾病，迫切需要了解精神分裂症潜在机制的新方法。 我们建议开发果蝇作为模型系统，研究这些疾病的潜在血清素神经化学。 该模型系统的开发和利用将导致用于治疗这些病症的治疗剂的新靶点的发现率提高。