Combining mammalian and Drosophila systems to study neuropsychiatric disorders

描述（由申请人提供）：该项目的总体目标是建立和追求一种创新方法，将哺乳动物系统中的发现研究与强大遗传模式生物果蝇中的翻译和功能研究相结合，作为一种新的策略来识别和表征精神病发展过程中发生的行为变化的基因和蛋白质。在寻找新的医学疗法，特别是涉及血清素的中枢神经系统疾病（如精神分裂症、精神病和抑郁症）的治疗方法时，人们越来越认识到，识别单一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，并且越来越被认为是一个关键和动态的研究领域，因为它将特定的分子靶标置于整体生物化学作用的背景下。了解特定生物系统中导致输出改变（例如行为改变）的组件之间的复杂相互作用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，分子事件，如基因表达的变化，在特定区域的大脑异常的5-羟色胺受体激活的影响，代表分子直接参与，或调节信号转导网络的基础上正常的认知过程，当干扰导致神经精神疾病。在这里，我们提出了一系列的实验系统为基础的方法，以确定特定的基因和蛋白质的功能和行为的作用，响应特定的神经递质受体的药理学激活在大鼠大脑的前额叶皮层在一个拟议的动物模型的神经化学和遗传事件的基础精神病和精神分裂症。我们将：1）通过功能基因组学、蛋白质组学和基因表达分析，确定大鼠前额皮质特定区域中额外的、可能更相关的基因和蛋白质; 2）在果蝇（Drosophila melanogaster）的翻译研究中，检查这些基因和蛋白质在行为中的功能作用。我们坚信，这种基于多学科系统的方法将哺乳动物CNS药理学和我们强大的遗传果蝇模型中的整个动物研究相结合，是实现我们目标的最佳途径。值得注意的是，我们的研究结果可能会为治疗精神分裂症和精神病等毁灭性疾病的治疗方法带来新的途径。公共卫生相关性：项目叙述：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到影响，美国经济每年损失近630亿美元。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。在这里，我们提出了一种基于系统的方法来确定潜在的分子和遗传因素的精神病相关疾病，涉及血清素通过执行目标发现和功能研究在基于神经网络的系统，并翻译功能的行为在强大的遗传模型果蝇。

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.