Combining mammalian and Drosophila systems to study neuropsychiatric disorders

结合哺乳动物和果蝇系统研究神经精神疾病

基本信息

批准号：
7663595
负责人：
CHARLES D NICHOLS
金额：
$ 35.16万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-07 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663595
关键词：
Affect Aggressive behavior American Animal Model Animals Area Behavior Behavioral Behavioral Genetics Biochemical Biological Biological Models Brain Brain region Candidate Disease Gene Central Nervous System Diseases Circadian Rhythms Cognitive Collection Complex Development Disease Drosophila genus Drosophila melanogaster Event Future Gene Expression Gene Proteins Genes Genetic Genetic Models Genetic Techniques Goals Homologous Gene Human Knowledge Laboratories Lead Learning Link Medical Memory Mental disorders Modeling Modification Molecular Molecular Genetics Molecular Target Mood Disorders Mus Neuropharmacology Neurotransmitter Receptor Output Pharmacology Positioning Attribute Prefrontal Cortex Process Proteomics Psychotic Disorders Publications Rattus Receptor Activation Recipe Regulation Research Resources Rodent Role Route Schizophrenia Sensory Process Series Serotonin Signal Transduction System Systems Biology Therapeutic Time Training Translating base biological systems cost depression effective therapy fly functional genomics innovation multidisciplinary neurochemistry neuropsychiatry novel novel strategies public health relevance research study serotonin receptor success tool translational study

项目摘要

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.

描述（由申请人提供）：该项目的总体目标是建立并采用一种创新的方法，将哺乳动物系统中的发现研究与强大的遗传模型有机体果蝇果蝇中的发现和功能研究相结合，作为识别和表征基因和蛋白质的新型策略，从而在精神病发展过程中发生了行为变化。在寻找新的医疗疗法，特别是涉及5-羟色胺，精神分裂症，精神病和抑郁症的中枢神经系统疾病的治疗方法时，人们越来越认识到，对单个生物学靶标的识别不太可能成为成功的综合秘诀；需要更广泛的观点。系统生物学就是一种这样的方法，并且越来越被认为是研究的关键和动态领域，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。了解给定生物系统中的组件之间的复杂相互作用，导致产出的修改（例如行为变化）可能是发现新疗法的重要途径。在该框架内，我们的潜在假设是，诸如基因表达的变化之类的分子事件受到大脑特定区域中异常的血清素受体激活的影响，代表直接参与或调节基于正常认知过程的信号转导网络的分子，这些分子会导致神经精神上的神经精神疾病。在这里，我们提出了一系列实验，遵循基于系统的方法来确定特定基因和蛋白质的功能和行为作用，这些实验对大鼠脑前额叶脑皮质中特定神经递质受体的药理激活响应在拟议的动物模型和精神病下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，蛋白质组学和基因表达分析，在大鼠前额叶皮层的特定区域中确定额外的，甚至更相关的基因和蛋白质； 2）检查这些基因和蛋白质在果蝇果蝇果蝇中的转化研究中的功能作用。我们坚信，这种基于多学科的基于系统的方法将哺乳动物CNS药理学和整个动物研究结合在我们强大的遗传果蝇模型中，是实现我们目标的最佳途径。值得注意的是，我们的结果可能会导致治疗诸如精神分裂症和精神病等毁灭性疾病的疗法途径。公共卫生相关性：项目叙事：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，付出了近630亿美元/年的经济。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。在这里，我们提出了一种基于系统的方法来识别与精神病相关疾病的分子和遗传因素，该方法通过在基于哺乳动物的系统中进行靶向发现和功能研究，并将功能转化为强大的遗传模型果蝇果蝇Melanogast的行为，涉及5-羟色胺。