Drosophila as a model genetic system to study neuropsychiatric disorders

描述(由研究人员提供)：我们研究的基本假设是，果蝇和其他动物模型中由作用于5-羟色胺受体的试剂引发的分子事件，代表了参与人类神经精神障碍发展和病因学的潜在候选者，重要的是，可能成为发现治疗新途径的目标。该项目的目标是开发果蝇，作为一种遗传上易处理的模型系统，以研究涉及5-羟色胺的人类神经精神疾病的分子机制。我们建议用特定的5-羟色胺能药物治疗果蝇，包括精神分裂症和抗精神病药物，以评估行为结果，并开发必要的遗传工具来阐明将受体激活与行为联系起来的途径。正如之前对果蝇从发育到药物反应的大多数研究过程所显示的那样，5-羟色胺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，我们建议通过分子、遗传学、药理学和行为学实验来研究果蝇中枢神经系统5-羟色胺系统的神经药理学、2)回路和3)行为，以建立果蝇5-羟色胺能功能的基础和知识库，以期发展果蝇作为模型遗传系统，与正在进行的哺乳动物目标识别实验相配合。总之，这些实验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。精神分裂症是一种令人衰弱的神经精神疾病，每100名美国人中就有一人受到影响，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，黑腹果蝇，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 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.