MicroRNA-Dependent Regulation of Synaptic and Behavioral Plasticity in Drosophila

果蝇突触和行为可塑性的 MicroRNA 依赖性调节

• 批准号: 9264036
• 负责人: Ronald L Davis
• 金额: $ 105.53万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264036
• 关键词: Address; Alleles; Animal Model; Architecture; Behavior; Behavioral; Behavioral Assay; Bioinformatics; Biological Assay; Brain; Brain region; Cellular Assay; Collaborations; Comparative Study; Complex; Country; Coupled; Data; Detection; Development; Dissection; Drosophila genus; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Genetic Translation; Genomics; Goals; Individual; Insecta; Institutes; Institution; Joints; Knowledge; Locomotion; Logic; Mammals; Maps; Mediating; Memory; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Computations; Molecular Genetics; Movement; Nervous system structure; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Output; Pathway interactions; Phenotype; Physiological; Proteins; RNA; Reagent; Regulation; Regulator Genes; Research Personnel; Series; Shapes; Signal Transduction; Sleep; Source; Stimulus; Synaptic plasticity; System; Technical Expertise; Techniques; Testing; Textiles; Time; Transgenic Organisms; Universities; Untranslated RNA; Validation; Work; analytical tool; behavioral plasticity; cell type; design; experimental study; genetic strain; improved; in vivo; innovation; loss of function; mRNA Stability; medical schools; mutant; nervous system development; neural circuit; neurodevelopment; overexpression; programs; protein expression; public health relevance; response; sensor; spatiotemporal; tool; transcriptome

 DESCRIPTION (provided by applicant): Precise temporal and spatial regulation of gene expression is essential to many aspects of nervous system development, function and plasticity. Among several classes of gene regulatory factors, non-coding RNAs have emerged as a rich potential source of regulatory mechanism in the central nervous system. In particular, microRNAs (miRs) provide sequence-specific control over target mRNA translation and stability that can tune the levels of downstream proteins quite precisely thus improving the stability and robustness of molecular networks. However, comprehensive analysis of miR function within the intact nervous system has been very challenging, leaving open key questions such as: How complex is the miR regulatory landscape for neural circuits that mediate essential behaviors? Are these miRs acting mainly during neural development or are they reused to manage ongoing neural circuit activity and adaptation to stimuli? To what extent are miR mechanisms utilized in many parts of the brain, or do they regulate distinct sets of target genes in different cell types and/or developmental stages? In order to address these questions, we have assembled a team of accomplished investigators prepared to work in unison using multiple robust behavioral and cellular assays as part of an integrated program. Our team includes Drs. David Van Vactor (Harvard Medical School), Leslie Griffith (Brandeis University), Ronald Davis (Scripps Institute), and Dennis Wall (Stanford University), who will each assume responsibility for key components of this joint program. We will use Drosophila as a model organism that offers many sophisticated genetic tools complementary to the innovative tools we will develop. Drosophila has proven to be particularly effective for identification and dissection of cellular and molecular mechanisms underlying well conserved behaviors. This model is also accessible to a full range of techniques for determining the detailed cellular and physiological phenotypes of mutants in specific pathways, thus offering a system ideal for mapping out miR functions on a comprehensive scale followed by mechanistic dissection that will effectively leverage a wealth of tools and knowledge. Together, we will (i) build and apply new genetic tools, (ii) apply these tools to identify miRs required in multiple neural circuits, (iii) discover the mechanisms and regulatory strategies for miR function in each context, and then (iv) compare each model to distinguish general and specific strategies and examine their conservation. This will be the first analysis of its kind in the nervous system. Our preliminary findings already identify convergence between different circuits that will prioritize our detailed studies of several miRs: miR-13, miR-92, miR-190 and let-7. Preliminary analysis of miR-92 already points to a series of highly conserved downstream genes implicated in both neural circuit development and synaptic plasticity from insects to mammals, providing a set of specific mechanistic hypotheses that we will test in the three model circuits to define the regulatory logic for each validated target.

 描述（由申请人提供）：基因表达的精确时间和空间调控对于神经系统发育、功能和可塑性的许多方面至关重要，在几类基因调控因子中，非编码RNA已成为丰富的潜在调控来源。特别是，microRNA (miR) 提供对靶 mRNA 翻译和稳定性的序列特异性控制，可以精确调节下游蛋白质的水平，从而提高分子网络的稳定性和鲁棒性。完整神经系统内的功能非常具有挑战性，留下了一些关键问题，例如：介导基本行为的神经回路的 miR 调节环境有多复杂？这些 miR 是否主要在神经发育过程中发挥作用，或者它们是否被重新用于管理正在进行的神经回路？ miR 机制在大脑的许多部分中发挥了多大的作用，或者它们在不同的细胞类型和/或发育阶段调节不同的靶基因组？由经验丰富的调查人员组成的团队准备齐心协力使用作为综合计划的一部分，我们的团队包括 David Van Vactor 博士（哈佛大学医学院）、Leslie Griffith（布兰迪斯大学）、Ronald Davis（斯克里普斯研究所）和 Dennis Wall（斯坦福大学）。我们将使用果蝇作为模型生物，为我们将开发的创新工具提供补充，果蝇已被证明对于细胞的识别和解剖特别有效。和分子 该模型还可以使用一系列技术来确定特定途径中突变体的详细细胞和生理表型，从而提供一个通过机械解剖全面绘制 miR 功能的理想系统。有效利用丰富的工具和知识，我们将 (i) 构建和应用新的遗传工具，(ii) 应用这些工具来识别多个神经回路所需的 miR，(iii) 发现 miR 功能的机制和调控策略。在每种情况下，以及然后（iv）比较每个模型以区分一般策略和特定策略，并检查它们的保守性，这将是神经系统中此类的首次分析。我们的初步研究结果已经确定了不同回路之间的收敛性，这将优先考虑我们对几种 miR 的详细研究。 ：miR-13、miR-92、miR-190 和 let-7 的初步分析已经指出一系列高度保守的下游基因与神经回路发育和突触可塑性有关。从昆虫到哺乳动物，提供了一组特定的机制假设，我们将在三个模型电路中测试这些假设，以确定每个经过验证的目标的调控逻辑。