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: 9910454
• 负责人: Ronald L Davis
• 金额: $ 94.17万
• 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/9910454
• 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; 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; Structure; Synaptic plasticity; System; Technical Expertise; Techniques; Testing; Textiles; Time; Transgenic Organisms; Universities; Untranslated RNA; Validation; Work; analytical tool; behavioral plasticity; cell type; computational platform; 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（由申请人证明）：基因表达的精确时间和空间调节对于神经系统的许多方面至关重要。中枢神经系统中的调节机制。留下关键问题，例如：内侧行为的神经回路的miR调节是多么复杂？在这些问题上，我们召集了一个有成就的调查人员，准备使用多个稳健的行为和蜂窝分析，屁股的一部分是我们团队的一部分。布兰代斯大学（Brandeis University），罗纳德·戴维斯（Ronald Davis）和丹尼斯·沃尔（Dennis Wall）（斯坦福大学）将对该联合计划的植物提供，该计划提供许多精致的基因工具，以互补我们将开发的创新工具。分子 机制保守的行为也是对特定途径中突变体的详细的Celluls生物学表型的全部技术，这些技术将有效地利用大量工具和知识。并在多个神经回路中应用新的遗传工具，（iii）在每种情况下发现MIR功能的机制和再培训，然后（IV）比较每个模型以区分一般策略并检查其构建其构建。神经系统中的种类。涉及神经旋转电路发育和从昆虫到哺乳动物的突触可塑性涉及的Nstream基因，提供了一组特殊的假设，这些假设在三个模型电路中定义了你的你的透明靶标。

项目成果

miRNA: local guardians of presynaptic function in plasticity and disease.

• DOI: 10.1080/15476286.2020.1871214
• 发表时间: 2021-07
• 期刊: RNA biology
• 影响因子: 4.1
• 作者: Woods BJ;Van Vactor D
• 通讯作者: Van Vactor D