MicroRNA Regulation of Biological Mechanisms

描述（由申请人提供）：对双链RNA （dsRNA）的保守生物反应介导对转座元件和病毒编码的寄生核酸的抗性。dsRNA切割成小干扰rna （sirna）会触发与sirna序列相关的基因的抑制。细胞产生的大量sirna与内源性mrna相对应，这些内源性sirna（内源性sirna）对其靶标进行适度抑制。这种沉默机制与另一个内源性调控过程有关，该过程抑制基因组中大多数蛋白质编码基因的表达。后一个过程是由基因组内数百个基因产生的microrna （mirna）引导的。我们研究的长期目标是了解内切sirna和mirna的生物学功能，并了解细胞行为的哪些方面是由小的非编码RNA调控控制的。为此，我们开发了整个果蝇和细胞的遗传、生化和细胞生物学方法来实现我们的目标。在之前的工作中，我们通过分子遗传学实验发现了内切sirna和miRNAs的调控功能。这些项目的结果是本提案研究目标的基础。我们的目标是：1)确定内切sirna如何使早期胚胎发育抵抗温度介导的环境变化；2)确定miRNAs是否通过创造蛋白质产生的阈值来抑制基因表达中的噪声；3)了解能量代谢如何控制miRNA活性，以及为什么在代谢受限的条件下，miRNA对细胞来说是必不可少的。对健康的重要性是多方面的。小rna调节生物体基因表达的能力表明，基本的理解将揭示影响生物学许多方面的控制机制。它将对miRNA基因经常发生突变的癌症等非传染性疾病产生影响。这项工作表明，mirna可以抑制个体之间的基因组变异对关键细胞行为变异的影响。在即将到来的个人基因组医学时代，了解基因组抑制的程度对于依赖基因组序列的疾病预测和预防方法至关重要。最后，小rna被用于疾病预后诊断，并作为疾病治疗药物被商业化开发，使对这些分子的基本了解成为重要的生物医学研究目标。

DESCRIPTION (provided by applicant): A conserved biological response to double-stranded RNA (dsRNA) mediates resistance to parasitic nucleic acids, encoded by transposable elements and viruses. Cleavage of dsRNA into small interfering RNAs (siRNAs) triggers repression of genes related by sequence to the siRNAs. A large number of siRNAs made by cells correspond to endogenous mRNAs, and these endogenous siRNAs (endo-siRNAs) trigger modest repression on their targets. This silencing mechanism is related to another endogenous regulatory process that represses the expression of most protein-coding genes in the genome. The latter process is guided by microRNAs (miRNAs), which are produced from hundreds of genes within the genome. The long-term goals of our research are to understand the biological functions of endo-siRNAs and miRNAs, and to understand what aspects of cell behavior are controlled by small non-coding RNA regulation. To this end, we have developed genetic, biochemical and cell biological methods in whole Drosophila and cells to achieve our goals. In previous work, we conducted molecular genetic experiments to discover regulatory functions of endo-siRNAs and miRNAs. Results of those projects are the basis for research aims in this proposal. Our aims are to: 1) determine how endo-siRNAs make early embryonic development resistant to environmental variation mediated by temperature, 2) determine whether miRNAs suppress noise in gene expression by creating thresholds of protein production, 3) understand how energy metabolism controls miRNA activity and why miRNAs become dispensable to cells under metabolically restricted conditions. The significance to health is manifold. The ability of small RNAs to regulate organismal gene expression suggests that basic understanding will reveal control mechanisms that influence many aspects of biology. It will have an impact on non-infectious diseases such as cancer, where miRNA genes are frequently mutated. This work shows that miRNAs can suppress the effects of genome variation between individuals on creating variation in critical cell behaviors. In the coming personal genome era of medicine, understanding the extent of genome suppression will be critical for disease prediction and prevention methods that rely on genome sequence. Finally, small RNAs are used diagnostically for disease prognosis, and are being commercially developed as disease therapeutics, making basic understanding of these molecules an important biomedical research goal.