MicroRNA regulation of biological mechanisms

描述(由申请人提供)： 最近，我们对一类被称为microRNAs的小型非编码RNAs的机制和生物学学到了很多。这类引人注目的RNA构成了人类基因组中2%的基因，它们抑制了蛋白质编码基因的表达。在动物物种中，这主要是通过关注3‘非翻译区含有互补序列的mRNA转录本的蛋白质合成来实现的。尽管目前还不可能准确地估计microRNA的调控程度，但多达30%的蛋白质编码基因被认为直接由microRNA控制。对模型生物的遗传学研究支持这样的观点，即microRNAs在细胞和生物生物学中扮演着不同的角色。我们对了解microRNAs调控的生物学后果感兴趣。为此，我们开发了遗传学和细胞生物学方法来研究整个果蝇组织和细胞中的单个microRNAs。我们将评估microRNAs缓冲基因调控的机制，以抵御环境扰动，如温度波动。这对神经系统的分化和发育很重要。将对调节该过程的上游调控途径进行评估，并将其与这些途径的已知生物学功能相关联。我们还对microRNAs的遗传缓冲的进化影响感兴趣。我们将在实验中测试microRNAs是否会缓冲动物种群在选择压力下的特征。最后，我们将使用定量实验方法和理论物理模型相结合的方法来评估microRNAs调节上皮组织中细胞形态发生的机制。对健康的意义是多方面的。MicroRNAs的综合作用影响了许多人类基因的表达，而microRNAs的错误调控似乎是癌症和病毒感染等各种疾病现象的基础。 公共卫生相关性： MicroRNAs是基因表达的调节者，它们的功能障碍与多种形式的癌症有关。此外，在多种病毒感染过程中，microRNAs发挥着重要的作用。这个项目是为了了解microRNAs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.