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，在果蝇中作用于5-羟色胺受体的特工和其他动物模型的分子事件代表了参与人类神经精神疾病的发展和病因的潜在候选者，这可能是针对新的Discemics of Discebosics of Disceics of Disceics的目标。 该项目的目的是开发果蝇，果蝇Melanogaster，作为一种可遗传障碍的模型系统，以研究涉及5-羟色胺的人类神经精神疾病的分子机制。 我们建议用特定的血清素能剂（包括精神病学和抗精神病药）来评估行为结果，并开发阐明将受体激活与行为联系起来的途径所需的遗传工具，以评估行为结局。 如果蝇中大多数先前研究的过程所示，从发育到药物反应，苍蝇和人之间的分子和细胞事件可能是高度保守的。 使用苍蝇来研究这些保守的神经化学事件，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，我们提出调查来通过表征：1）神经药理学，2）电路和3）使用分子，遗传学，药理和行为实验来奠定基础并创建在Drosophila中的知识基础，并建立在Drosophila中的知识基础，并建立在Drosophila中的知识基础，并建立在veement的知识基础上，并建立在Drosophila的知识基础上，并建立了一定的知识基础哺乳动物目标识别实验。 这些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，并且对于促进发现新型疗法靶标非常重要。 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，耗资近630亿美元/年的美国经济。 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。 我们建议开发果蝇果蝇果蝇，作为研究这些疾病的潜在5-羟色胺神经化学的模型系统。 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。