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Characterization of microRNAs expressed in the developing songbird brain

发育中鸣禽大脑中表达的 microRNA 的表征

基本信息

批准号：
7885493
负责人：
XIAOCHING LI
金额：
$ 21.3万
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：
2009-07-03 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Characterization of microRNAs expressed in the developing songbird brain Project Summary Many parallels are shared between language development in human children and song learning in songbirds. Thus songbirds provide a unique model system to study the molecular and cellular mechanisms controlling neural circuit development and vocal learning. MicroRNAs are a class of non-protein coding RNA molecules that regulate gene expression post transcriptionally in a wide array of biological events, especially during development. We plan to study the regulatory functions of miRNAs in neural development and plasticity in zebra finches, where both the song behavior and the underlying neural circuits have been extensively established. In this two-year exploratory project, we will focus on a systematic genome-wide characterization of miRNA expression in the zebra finch brain across a bird's entire life span. This project has two specific aims. In Specific Aim I, small RNA libraries from zebra finch brains at different developmental stages ranging from the early embryonic stage to old age will be made; the libraries will be sequenced using the ultra-high-throughput Solexa sequencing technology; miRNA candidate sequences will be annotated with Bioinformatic analysis. In Specific Aim II, Northern blot hybridization and in situ hybridization will be performed for a selected group of miRNA candidates to validate their expression and to map their expression to the song control nuclei during circuit development. Priorities will be given to miRNAs that have been implicated in neural development, plasticity, and developmental disorders, as well as miRNAs whose predicted target genes have been implicated in these processes. This initial experiment will generate necessary information (e.g., the temporal and spatial miRNA expression in the developing song system), thus setting up the stage for our longer-range research on the roles of miRNAs in neural development/plasticity and in developmental disorders. A systematic genome-wide miRNA profiling in the songbird brain may extend the miRNA repertoire and their expression patterns during development may provide insights to their functions. In addition to our own work, the experimentally identified miRNA sequences may be used in the annotation of the zebra finch genome sequence. Also, comparative analysis of miRNAs in songbirds and other species may add to our understanding of the evolution of miRNA gene family in general. PUBLIC HEALTH RELEVANCE: MicroRNAs regulate gene expression and play important roles in brain development; therefore, understanding the molecular mechanisms of miRNA function is essential for understanding normal brain developmental processes and developmental disorders. The importance of miRNA research has been exemplified by the fact that currently there are already several RNAi-based drugs being tested in clinical trials for illnesses ranging from cancer to eye disease. Results from our experiment, where miRNAs are studied in the context of neural circuit development and vocal learning, may contribute to understanding and eventually curing developmental disorders in human children (e.g., autism, dyslexia, etc).

项目概述：人类儿童的语言发展与鸣禽的鸣叫学习之间有许多相似之处。因此，鸣禽为研究控制神经回路发育和声乐学习的分子和细胞机制提供了一个独特的模型系统。MicroRNAs是一类非蛋白质编码RNA分子，在广泛的生物事件中，特别是在发育过程中，通过转录调控基因表达。我们计划研究mirna在斑马雀神经发育和可塑性中的调节功能，斑马雀的鸣叫行为和潜在的神经回路已经广泛建立。在这个为期两年的探索性项目中，我们将专注于在斑胸草雀整个生命周期中对其大脑中miRNA表达的系统全基因组表征。这个项目有两个具体目标。在Specific Aim I中，将从不同发育阶段（从早期胚胎期到老年）的斑胸草雀大脑中提取小RNA文库；这些文库将使用超高通量Solexa测序技术进行测序；miRNA候选序列将通过生物信息学分析进行注释。在Specific Aim II中，将对选定的一组候选miRNA进行Northern blot杂交和原位杂交，以验证其表达，并将其表达映射到电路发育过程中的song控制核。将优先考虑与神经发育、可塑性和发育障碍有关的mirna，以及与这些过程有关的预测靶基因的mirna。这个初步的实验将产生必要的信息（例如，发育中的歌唱系统中miRNA的时空表达），从而为我们对miRNA在神经发育/可塑性和发育障碍中的作用的长期研究奠定基础。在鸣禽大脑中进行系统的全基因组miRNA分析可以扩展miRNA库，并且它们在发育过程中的表达模式可以提供对其功能的见解。除了我们自己的工作外，实验鉴定的miRNA序列可用于斑胸草雀基因组序列的注释。此外，对鸣禽和其他物种的miRNA进行比较分析，可能会增加我们对miRNA基因家族进化的总体理解。公共卫生相关性：MicroRNAs调节基因表达并在大脑发育中发挥重要作用；因此，了解miRNA功能的分子机制对于理解正常的大脑发育过程和发育障碍至关重要。目前已经有几种基于rna的药物在从癌症到眼病的临床试验中进行测试，这一事实证明了miRNA研究的重要性。我们在神经回路发育和声音学习的背景下研究mirna的实验结果，可能有助于理解并最终治疗人类儿童的发育障碍（如自闭症、阅读障碍等）。