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）：该项目的目的是开发果蝇，果蝇Melanogaster，作为一种遗传障碍的模型系统，用于研究涉及5-羟色胺的人类神经精神疾病的分子机制，例如Schizizophrenia和Schizophrenia和抑郁症。 我们建议用特定的血清素能精神分子治疗果蝇，从而产生可观察到的行为效应。 如先前研究的大多数途径所示，将血清素受体相互作用与行为联系起来的分子事件可能在苍蝇和人之间高度保守。 使用苍蝇来研究这些保守的神经化学事件，使得非常有力的遗传技术迅速阐明了关键途径和分子，否则这些途径和分子可能会花费数年，而基于传统的基于哺乳动物的方法，这些途径和分子可以花费更大的成本。 重要的是，蝇被认为可以表达哺乳动物5-HT2受体的功能性直系同源物，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直系同源物，所有这些都在各种人类的Neuropcy中都强烈地构成了各种各样的人。 在这里，我们提出的研究表征：1）行为，2）电路和3）果蝇中CNS 5-羟色胺系统的神经药理学，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。 这些果蝇研究结合了持续提出的哺乳动物靶标识别实验，共同构成了一种基于系统的新方法，探索与人类神经精神疾病相关的神经化学事件，并且非常重要，对于促进新型治疗靶标的发现。 关于公共卫生的总结：精神分裂症是一种使人衰弱的神经精神疾病，每100名美国人中约有1个，付出了近630亿美元/年的经济。 为了进一步理解和治疗这种疾病以及其他精神疾病，迫切需要采取新的理解基本精神分裂症机制的方法。 我们建议将果蝇作为模型系统发展，以研究这些疾病的潜在5-羟色胺神经化学。 该模型系统的开发和利用将导致疗法治疗这些疾病的新型靶标的发现率提高。