Functional genomics to identify miRNA targets in the developing face

描述（由申请人提供）：颅面发育缺陷是常见的，影响约1/100的人类婴儿，具有较高的经济和人力成本。通过更好地了解面部发育的机制，我们希望制定更好的预防，诊断和治疗策略。FaceBase目前拥有用于小鼠面部发育的启动子，转录本和microRNA（miR）的高通量数据。为了有效地利用这些数据来理解遗传程序、细胞相互作用以及面部形态发生的机制，它们必须相互整合，并与更普遍的知识相结合。microRNAs（miRNAs）是遗传程序的重要组成部分，在面部发育中具有关键作用。它们通常通过下调靶信使RNA（mRNA）起作用。平均miRNA靶向超过200种mRNA，并且许多mRNA由多个miRNA调节。给定的miRNA的靶点通常在功能上是相关的，因此miRNA调节生物学功能以及单个基因。基因组水平miRNA研究的挑战是识别每个miRNA靶向的单个基因和生物学功能。该提案利用现有的mRNA和miRNA表达数据从发展中的小鼠脸，并将其与功能基因组学知识，提供一个系统水平的观点的作用（S）的miRNA在面部发育。计算方法基于这样的假设，即miRNAs通过协调调节细胞分化和/或细胞命运来协调遗传程序。 功能相关的基因组。它识别并分配可能受miRNA调控的基因、途径和生物过程的概率。然后在颅神经嵴细胞系中测试这些预测。通过比较计算的概率与验证率，这将为miRNAs协调遗传程序的一般假设提供统计检验。这些数据将概述miRNAs在面部发育中的作用，以及哪些miRNAs可能具有最深远的影响。他们还将确定介导这些影响的基因、途径和生物过程。鉴于microRNA可以在体外和体内相对容易地操作，这些信息有可能导致更有效的组织工程治疗人类面部出生缺陷。

DESCRIPTION (provided by applicant): Craniofacial developmental defects are common, affecting about 1 in 100 human infants, with high financial and human costs. By better understanding the mechanisms of facial development, we hope to develop better prevention, diagnostic and treatment strategies. FaceBase currently houses high-throughput data on promoters, transcripts and microRNAs (miRs) that are used in mouse facial development. To effectively use these data to understand the genetic programs, the cellular interactions, and hence the mechanisms underlying morphogenesis of the face, they must be integrated amongst themselves and with more general knowledge. microRNAs (miRNAs) are an important component of genetic programs and have critical roles in facial development. They generally act through down-regulating target messenger RNAs (mRNAs). The average miRNA targets over 200 mRNAs, and many mRNAs are regulated by multiple miRNAs. The targets of a given miRNA are generally functionally related, so miRNAs regulate biological functions as well as of individual genes. The challenge for genomic-level miRNA studies is to identify the individual genes and biological functions that are targeted by each miRNA. This proposal utilizes existing mRNA and miRNA expression data from the developing mouse face and integrates it with functional genomics knowledge to provide a systems-level view of the role(s) of miRNAs in facial development. The computational approach is based on the hypothesis that miRNAs orchestrate genetic programs for cell fate and/or differentiation through coordinated regulation of suites of functionally related genes. It identifies and assigns probabilities to genes, pathways and biological processes that are likely to be regulated by miRNAs. It then tests these predictions in a cranial neural crest cell line. By comparing computed probabilities to validation rates, this will provide a statistical test for the general hypothesis that miRNAs orchestrate genetic programs. These data will provide an overview of the role(s) of miRNAs in facial development as well as which miRNAs are likely to have the most profound effects. They will also identify the genes, pathways and biological processes that mediate those effects. Given the relative ease with which microRNAs can be manipulated in vitro and in vivo, this information has the potential to lead to more effective tissue engineering treatments for human facial birth defects.