MicroRNA genes and their functions

描述(申请人提供)：RNA分子在调节真核基因表达中可能扮演的角色已经转移到中心舞台上。最近发现，在线虫发育过程中控制细胞分裂时间的两个小的调控RNA，Lin-4 RNA和let-7 RNA，是一大类21到24个核苷酸的非编码RNA的成员，称为microRNAs(MiRNAs)。到目前为止，在线虫、果蝇和人类中已经报道了数十个miRNA基因。这项建议侧重于这类新发现的基因的基因组学和功能基因组学，其广泛的、长期的目标是了解RNA在调节基因表达中的作用。具体目标是：1)使用分子方法识别更多的miRNA基因，2)开发和应用生物信息学工具来识别miRNA基因，3)检测miRNA基因或功能中断的后果。AIMS#1和#2的实验将识别和检测数百个miRNA基因的表达，包括线虫和鱼类中的大多数miRNA基因。他们还将检测老鼠和人类的候选基因。因此，它们将极大地扩展数据库中miRNA基因的注释--这是所有生物学家的资源，对于那些关注真核基因调控、发育和疾病的人来说具有特别的价值。AIM#1的实验还将在植物和真菌中寻找miRNAs，努力扩大这些非编码RNA的已知系统发育分布。Aim#3的实验将试图敲除线虫中的100个miRNA基因。他们还将探索抑制斑马鱼miRNA功能的方法。MiRNA干扰的表型将提供关键的见解，了解哪些调控网络包括miRNAs，以及有多大比例的miRNAs在发育、分化和其他过程中具有可识别的、非冗余的作用。由于人们对这类新发现的基因知之甚少，因此人们对它们可能在人类体内发挥作用的过程进行了大量的猜测。在模式生物中识别miRNA基因并调查它们的功能将为理解miRNAs在人类中的作用以及了解它们的功能障碍如何导致疾病提供重要的见解和试剂。

DESCRIPTION (provided by applicant): The role that RNA molecules might be playing in modulating eukaryotic gene expression has moved to center stage. It has recently been discovered that two small regulatory RNAs, lin-4 RNA and let-7 RNA, which control the timing of cell divisions during C. elegans development, are members of a large class of 21- to 24-nt noncoding RNAs, called microRNAs (miRNAs). Thus far, dozens of miRNA genes have been reported in C. elegans, Drosophila, and humans. This proposal focuses on the genomics and functional genomics of this newly identified class of genes, with the broad, long-term objective of understanding the roles of RNA in regulating gene expression. The specific aims are: 1) to use molecular methods to identify additional miRNA genes, 2) to develop and apply bioinformatic tools for identifying miRNA genes, and 3) to examine the consequence of disrupting miRNA genes or functions.Experiments of Aims #1 and #2 will identify and examine the expression of hundreds of miRNA genes, including most of the miRNA genes in nematodes and fish. They will also detect mouse and human candidate genes. Thus, they will greatly expand the annotation of miRNA genes in the databases-a resource for all biologists, and of particular value for those concerned with eukaryotic gene regulation, development, and disease. Experiments of Aim #1 will also search for miRNAs in plants and fungi, in an effort to expand the known phylogenetic distribution of these noncoding RNAs. Experiments of Aim #3 will attempt to knockout 100 miRNA genes in C. elegans. They will also explore methods for inhibiting miRNA function in zebrafish. The phenotypes of miRNA disruptions will provide key insights as to which regulatory networks include miRNAs and what fraction of miRNAs have discernable, non-redundant roles in development, differentiation and other processes. Because so little is known about this newly identified class of genes, speculation is rife on the processes in which they might function in humans. Identifying the miRNA genes and surveying their functions in model organisms will provide important insights and reagents for understanding the roles of miRNAs in humans and learning how their dysfunction might contribute to disease.