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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

基本信息

批准号：
7392371
负责人：
CHARLES D NICHOLS
金额：
$ 20.83万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392371
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

项目摘要

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，在果蝇和其他动物模型中，由作用于5 -羟色胺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发展和病因学的潜在候选者，重要的是，可能是发现治疗新途径的目标。这个项目的目标是发展果蝇，黑胃果蝇，作为一个遗传上可处理的模型系统来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治疗苍蝇，包括拟精神病药物和抗精神病药物，以评估行为结果，并开发必要的遗传工具来阐明连接受体激活与行为的途径。从果蝇的发育到对药物的反应，在果蝇和人类之间，5 -羟色胺能功能背后的分子和细胞事件可能是高度保守的。利用果蝇来研究这些保守的神经化学事件，可以利用极其强大的基因技术来快速阐明关键的途径和分子，否则，通过传统的基于哺乳动物的方法，可能需要数年时间，而且成本要高得多。重要的是，果蝇被认为表达了哺乳动物5-HT2受体的功能同源物，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同源物，所有这些受体都与各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、药理学和行为实验，通过表征果蝇CNS血清素系统的神经药理学，2)电路和3)行为，为果蝇血清素能功能奠定基础和建立知识库，以开发果蝇作为模型遗传系统，以配合正在进行的哺乳动物靶标识别实验。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疾病相关的神经化学事件，并将对促进治疗新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，每100个美国人中就有一个受其影响，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，迫切需要新的方法来理解精神分裂症的潜在机制。我们建议开发果蝇，即黑腹果蝇，作为研究这些疾病潜在的血清素神经化学的模型系统。该模型系统的开发和利用将提高治疗这些疾病的新靶点的发现率。