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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：
8233498
负责人：
CHARLES D NICHOLS
金额：
$ 34.77万
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233498
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 Depression 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 abstracting base biological systems cost effective therapy fly functional genomics innovation multidisciplinary neurochemistry neuropsychiatry novel novel strategies research study serotonin receptor success tool translational study

项目摘要

Project Abstract: 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.

项目摘要：该项目的总体目标是建立并追求一种创新方法，将哺乳动物系统的发现研究以及强大的转化和功能研究遗传模型生物果蝇作为识别和表征基因的新策略以及精神病发展过程中发生的行为变化背后的蛋白质。在寻找新的医学疗法，特别是中枢神经疾病的治疗方法涉及血清素的系统，如精神分裂症、精神病和抑郁症，越来越多认识到识别单一生物靶点不太可能成为成功的秘诀；一个需要更广阔的视野。系统生物学就是这样一种方法，并且已经越来越多地被被认为是一个重要且充满活力的研究领域，因为它将特定的分子靶标置于一个整体生化作用的背景。了解组件之间复杂的交互在给定的生物系统中，导致输出改变，例如行为改变，可能是发现新疗法的重要途径。在这个框架内，我们的底层假设是分子事件，例如基因表达变化，受到异常血清素的影响大脑特定区域的受体激活代表直接参与的分子，或调节作为正常认知过程基础的信号转导网络，当受到干扰时导致神经精神疾病。在这里，我们提出了一系列基于系统的实验确定响应的特定基因和蛋白质的功能和行为作用的方法大鼠大脑前额皮质特定神经递质受体的药理学激活拟议的精神病背后的神经化学和遗传事件的动物模型精神分裂症。我们将：1）识别额外的，也许更相关的基因和蛋白质通过功能基因组、蛋白质组和基因研究大鼠前额皮质的特定区域表达分析； 2）检查这些基因和蛋白质在行为中的功能作用果蝇的转化研究。我们坚信，这结合哺乳动物中枢神经系统药理学和整体的多学科系统方法在我们强大的遗传果蝇模型中进行的动物研究是实现我们目标的最佳途径目标。值得注意的是，我们的结果可能会为治疗这种毁灭性的疾病带来新的治疗途径。精神分裂症和精神病等疾病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor.

DOI：
10.1007/s00018-011-0789-0
发表时间：
2012-02
期刊：
CELLULAR AND MOLECULAR LIFE SCIENCES
影响因子：
8
作者：
Luo, Jiangnan;Becnel, Jaime;Nichols, Charles D.;Nassel, Dick R.
通讯作者：
Nassel, Dick R.

Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain.

DOI：
10.1016/j.ebiom.2016.08.049
发表时间：
2016-09
期刊：
EBIOMEDICINE
影响因子：
11.1
作者：
Martin, David A.;Nichols, Charles D.
通讯作者：
Nichols, Charles D.

DREADDs in Drosophila: a pharmacogenetic approach for controlling behavior, neuronal signaling, and physiology in the fly.

果蝇中的Dreadds：一种用于控制行为，神经元信号和生理学的药物遗传学方法。

DOI：
10.1016/j.celrep.2013.08.003
发表时间：
2013-09-12
期刊：
Cell reports
影响因子：
8.8
作者：
Becnel J;Johnson O;Majeed ZR;Tran V;Yu B;Roth BL;Cooper RL;Kerut EK;Nichols CD
通讯作者：
Nichols CD

5-HT stimulation of heart rate in Drosophila does not act through cAMP as revealed by pharmacogenetics.