MicroRNA regulation of biological mechanisms

描述（由申请人提供）： 最近，我们对一类称为microRNA的小的非编码RNA的机制和生物学有了很多了解。这类RNA占人类基因组中基因的2%，它们抑制蛋白质编码基因的表达。这在动物物种中主要是通过从mRNA转录物中减少蛋白质合成来实现的，所述mRNA转录物在其3'非翻译区中含有互补序列。尽管目前还不可能准确估计microRNA的调控程度，但据信高达30%的蛋白质编码基因直接受microRNA控制。模式生物的遗传学研究支持microRNA在细胞和生物体生物学中发挥不同作用的观点。我们有兴趣了解microRNA调控的生物学后果。为此，我们开发了遗传和细胞生物学方法来研究整个果蝇组织和细胞中的单个microRNA。我们将评估microRNA缓冲基因调控对抗环境扰动（如温度波动）的机制。这对神经系统的分化和发育至关重要。将评价调节该过程的上游调节途径，并将其与这些途径的已知生物学功能相关联。我们也对microRNA基因缓冲的进化意义感兴趣。我们将通过实验测试microRNA是否在动物种群的选择压力下缓冲性状。最后，我们将使用定量实验方法和理论物理模型相结合，评估microRNA调节上皮组织细胞形态发生的机制。对健康的意义是多方面的。microRNA的组合效应影响许多人类基因的表达，并且microRNA的失调似乎是多种疾病现象如癌症和病毒感染的基础。 公共卫生相关性： microRNA是基因表达的调节因子，它们的功能障碍与多种形式的癌症有关。此外，microRNA在许多病毒感染过程中发挥重要作用。该项目旨在了解microRNA如何控制基因表达及其在体内的自然功能。

DESCRIPTION (provided by applicant): We have learned a great deal recently about the mechanism and biology of a class of small non-coding RNAs called microRNAs. This remarkable class of RNAs constitute 2% of the genes in the human genome, and they repress the expression of protein-coding genes. This is achieved in animal specieis primarily by attenation of protein synthesis from mRNA transcripts which contain complementary sequence in their 3' untranslated regions. Although it is impossible yet to accurately estimate the extent of microRNA regulation, up to 30% of protein- coding genes are thought to be directly controlled by microRNAs. Genetic studies in model organisms support the notion that microRNAs play diverse roles in cell and organismal biology. We are interested in understanding the biological consequences of regulation by microRNAs. To this end, we have developed genetic and cell biological methods to study individual microRNAs in whole Drosophila tissues and cells. We will evaluate the mechanisms by which microRNAs buffer gene regulation against environmental perturbation such as temperature fluctuation. This is important for differentiation and development of the nervous system. The upstream regulatory pathways that regulate the process will be evaluated, and correlated to known biological functions of these pathways. We are also interested in the evolutionary implications of genetic buffering by microRNAs. We will experimentally test whether microRNAs buffer traits under selective pressure upon animal populations. Finally, we will evaluate the mechanisms by which microRNAs regulate cell morphogenesis in epithelial tissues, using a combination of quantitative experimental methods and theoretical physical modeling. The significance to health is manifold. The combined effects of microRNAs affect the expression of many human genes, and misregulation of microRNAs appear to underlie diverse disease phenomena such as cancer and virus infection. PUBLIC HEALTH RELEVANCE: MicroRNAs are regulators of gene expression, and their dysfunction is linked to diverse forms of cancer. Additionally, microRNAs play important functions during infection by numerous viruses. This project is to understand how microRNAs control gene expression and their natural functions within the body.