Combining mammalian and Drosophila systems to study neuropsychiatric disorders

描述(申请人提供)：这个项目的总体目标是建立和追求一种创新的方法，将哺乳动物系统中的发现研究与强大的遗传模式生物黑腹果蝇的翻译和功能研究相结合，作为一种新的策略，以识别和表征精神病发展过程中发生的行为变化的潜在基因和蛋白质。在寻找新的医学疗法，特别是治疗涉及5-羟色胺的中枢神经系统疾病，如精神分裂症、精神病和抑郁症的过程中，越来越多的人认识到，确定单一的生物靶点不太可能是成功的秘诀；需要更广泛的视角。系统生物学就是这样一种方法，由于它将特定的分子靶标置于整体生化作用的背景下，因此越来越被认为是一个关键的和动态的研究领域。了解给定生物系统中各成分之间的复杂相互作用，从而导致输出的改变，如行为的变化，可能是发现新疗法的重要途径。在这个框架内，我们的基本假设是，受大脑特定区域5-羟色胺受体异常激活影响的分子事件，如基因表达变化，代表着直接参与或调节信号转导网络的分子，这些网络是正常认知过程的基础，当受到干扰时，会导致神经精神障碍。在这里，我们提出了一系列基于系统的方法来确定特定基因和蛋白的功能和行为作用，这些基因和蛋白响应于大鼠大脑前额叶皮质特定神经递质受体的药物激活，在一个拟议的精神病和精神分裂症潜在的神经化学和遗传事件的动物模型中。我们将：1)通过功能基因组、蛋白质组和基因表达分析，在大鼠前额叶皮质的特定区域识别额外的、可能更相关的基因和蛋白质；2)在果蝇黑腹果蝇的翻译研究中检测这些基因和蛋白质在行为中的功能作用。我们坚信，在我们强大的遗传果蝇模型中，这种基于多学科系统的方法结合了哺乳动物中枢神经系统药理学和整个动物研究，是实现我们目标的最佳途径。值得注意的是，我们的结果可能会为治疗精神分裂症和精神病等破坏性疾病开辟新的途径。公共卫生相关性：项目叙述：精神分裂症是一种衰弱的神经精神疾病，大约每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。在这里，我们提出了一种基于系统的方法，通过在哺乳动物系统中进行靶标发现和功能研究，并在强大的遗传模型黑腹果蝇中将功能转化为行为，来识别涉及5-羟色胺的精神病相关疾病潜在的分子和遗传因素。

DESCRIPTION (provided by applicant): The overall goals of this project are to establish and pursue an innovative approach combining discovery studies in mammalian systems with translational and functional studies in the powerful genetic model organism Drosophila melanogaster as a novel strategy to identify and characterize genes and proteins underlying the behavioral changes that occur during the development of psychosis. In the search for new medical therapies, and in particular treatments for disorders of the central nervous system involving serotonin, like schizophrenia, psychosis, and depression, there has been increasing recognition that identification of a single biological target is unlikely to be a recipe for success; a broader perspective is required. Systems biology is one such approach, and has been increasingly recognized as a crucial and dynamic area of research, as it places specific molecular targets within a context of overall biochemical action. Understanding the complex interactions between the components within a given biological system that lead to modifications in output, such as changes in behavior, may be important avenues of discovery to identify new therapies. Within this framework, our underlying hypothesis is that molecular events, such as gene expression changes, influenced by aberrant serotonin receptor activation in specific regions of the brain, represent molecules that directly participate in, or regulate signal transduction networks that underlie normal cognitive processes that when perturbed lead to neuropsychiatric disorders. Here, we propose a series of experiments following a systems based approach to determine the functional and behavioral role of specific genes and proteins that respond to pharmacological activation of specific neurotransmitter receptors in the prefrontal cortex of rat brain in a proposed animal model of the neurochemical and genetic events underlying psychosis and schizophrenia. We will: 1) Identify additional, and perhaps more relevant, genes and proteins in specific regions of the rat prefrontal cortex through functional genomic, proteomic, and gene expression analysis; 2) Examine the functional role of these genes and proteins in behaviors in translational studies in the fruit fly, Drosophila melanogaster. We strongly believe that this multidisciplinary systems-based approach combining mammalian CNS pharmacology and whole animal studies in our powerful genetic Drosophila model, is the best route to follow to achieve our goals. Significantly, our results may lead to novel avenues for therapeutics to treat such devastating diseases as schizophrenia and psychosis. PUBLIC HEALTH RELEVANCE: Project Narrative: 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 disorder, as well as other psychiatric disorders. Here, we are proposing a systems based approach to identify molecular and genetic factors underlying psychosis related disorders that involve serotonin by performing target discovery and functional studies in mammalian-based systems, and translating function to behavior in the powerful genetic model Drosophila melanogaster.