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: 7257365
• 负责人: CHARLES D NICHOLS
• 金额: $ 19.17万
• 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/7257365
• 关键词: Affect; American; Animal Model; Antipsychotic Agents; Behavior; Behavioral; Behavioral Assay; Biological Models; Brain; Complex; Condition; Development; Disease; Dopamine; Drosophila genus; Drosophila melanogaster; Etiology; Event; Foundations; Gene Proteins; Genetic; Genetic Models; Genetic Techniques; Goals; Human; Individual; Investigation; Lead; Link; Maps; Mental Depression; Mental disorders; Metabotropic Glutamate Receptors; Methods; Modeling; Molecular; Molecular Genetics; N-Methylaspartate; Neuropharmacology; Orthologous Gene; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Process; Range; Rate; Receptor Activation; Research; Research Personnel; Role; Schizophrenia; Serotonin; Serotonin Agents; System; Therapeutic; base; behavior influence; cost; fly; gamma-Aminobutyric Acid; in vivo; knowledge base; neurochemistry; neuropsychiatry; novel; novel strategies; receptor; research study; response; serotonin receptor; therapeutic target; tool

DESCRIPTION (provided by investigator): The fundamental hypothesis of our research is that molecular events initiated by agents acting at serotonin receptors in Drosophila, and other animal models, represent potential candidates for involvement in the development and etiology of neuropsychiatric disorders in humans, and importantly, may be targets for new avenues of discovery for therapeutics. 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. We propose to treat flies with specific serotonergic agents, including psychotomimetics and antipsychotics, to assess behavioral outcomes, and to develop the genetic tools necessary to elucidate the pathways linking receptor activation with behavior. As shown with most previously studied processes in Drosophila, ranging from development to drug response, the molecular and cellular events underlying serotonergic function 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 develop this fly model by characterizing the: 1) neuropharmacology, 2) circuitry, and 3) behaviors of the Drosophila CNS serotonin system using molecular, genetic, pharmacological, and behavioral experiments to lay the foundation and create a knowledge base of serotonergic function in Drosophila, with a view toward developing the fly as a model genetic system to use in concert with ongoing proposed mammalian target identification experiments. Together, these experiments 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. 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, Drosophila melanogaster, 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（由研究者提供）：我们研究的基本假设是，作用于果蝇和其他动物模型中血清素受体的药物引发的分子事件代表了参与人类神经精神疾病的发展和病因学的潜在候选者，并且重要的是，可能是治疗学发现新途径的目标。 该项目的目标是开发果蝇（Drosophila melanogaster）作为遗传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的分子机制。 我们建议用特定的血清素能药物（包括拟精神病药和抗精神病药）治疗果蝇，以评估行为结果，并开发必要的遗传工具来阐明受体激活与行为之间的联系途径。 正如大多数先前研究的果蝇过程所示，从发育到药物反应，血清素能功能的分子和细胞事件在果蝇和人类之间可能是高度保守的。 利用果蝇来研究这些保守的神经化学事件，发挥了极其强大的遗传技术的作用，可以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，而且成本要高得多。 重要的是，果蝇被认为表达哺乳动物 5-HT2 受体的功能直系同源物，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疾病密切相关。 在这里，我们建议通过利用分子、遗传、药理学和行为实验来表征果蝇 CNS 血清素系统的 1) 神经药理学，2) 电路和 3) 行为来开发这种果蝇模型，以奠定基础并创建果蝇血清素能功能的知识库，以期将果蝇开发为模型遗传系统，与正在进行的提议相结合使用 哺乳动物目标识别实验。 这些实验共同形成了一种新的基于系统的方法，用于探索与人类神经精神疾病相关的神经化学事件，并且对于促进新治疗靶点的发现具有重要意义。 精神分裂症是一种使人衰弱的神经精神疾病，大约每 100 名美国人中就有一人患有精神分裂症，每年给美国经济造成近 630 亿美元的损失。 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（Drosophila melanogaster）作为模型系统来研究这些疾病的基础血清素神经化学。 该模型系统的开发和利用将提高治疗这些疾病的新靶标的发现率。