Cancer and Gene Regulation by Short RNAs

癌症是一种主要的疾病负担，改变这种情况的一个希望是通过 更好地了解这种疾病。关于哺乳动物短RNA活性的最新发现 可能为癌症提供新的见解和新的治疗方法。癌症是一种基因失调的疾病 由突变和表观遗传变化引起的。现在已知短RNA在基因水平上调节基因 信使核糖核酸降解，主要由siRNAs，信使核糖核酸翻译，主要由微RNA，以及信使核糖核酸 转录，主要是通过重复相关的短干扰RNA(RasiRNAs)。最近的结果来自 生物信息学研究表明，大约20%的哺乳动物mRNAs可能受 我的核糖核酸。此外，有强有力且迅速增长的证据表明，miRNA的变化 调控与恶变有关，事实上可能是致癌的关键事件 转型。关于短RNA在转录水平沉默中的潜在作用，我们知之甚少 这些细胞中染色质的含量。有可能一些表观遗传变化和基因组不稳定 常见的癌症可能由RNAi相关途径引导。RNA干扰革命的一部分 是从载体中表达短发夹状RNA的能力，以产生沉默特定基因的siRNA。 首先，与JACKS和LEES项目合作，我们将开发表达shRNA的慢病毒载体 以一种受调控的方式使用tet激活的POL II转录。第二，我们将使用一个非常敏感的克隆 短RNA技术，用于分析T细胞群体在发育过程中的表达。 特定miRNAs的活动将与这一已定义途径中的已知发育转变有关。 此外，T细胞淋巴瘤和其他肿瘤细胞中的短RNA的性质将通过 与其他项目的协作。两种染色质修饰对重复序列的沉默 而DNA甲基化在胚胎干细胞中经常被观察到。我们将克隆短RNA 诱导ES细胞从重复序列中高水平表达RNA的研究 短RNA在转录水平的基因沉默中的作用。两国之间的关系 这些ES细胞中重复和独特序列的重新沉默以及克隆的短RNA序列 将会被调查。此外，这些过程对Dager、ArgAerte和其他RNAi相关的过程的依赖 基因将被确定。我们还将确定miRNAs集群的功能，即 仅在胚胎干细胞和胚胎组织中表达。最后，我们发现视网膜母细胞瘤 (Rb)途径和RNAi途径调节华支睾吸虫肠道上皮细胞有丝分裂后核分裂。 优雅女装。我们将研究相关通路是否对调节细胞分裂起重要作用。 哺乳动物细胞。

Cancer is a major disease burden and one hope of changing this is to develop new treatments through a better understanding of the disease. Recent discoveries concerning the activities of short RNAs in mammals may provide both new insights and new treatments of cancer. Cancer is a disease of gene dysregulation caused by mutations and epigenetic changes. Short RNAs are now known to regulate genes at the levels of mRNA degradation, primarily by siRNAs, mRNA translation, primarily by microRNAs, and mRNA transcription, primarily by repeat-associated short interfering RNAs (rasiRNAs). Recent results from bioinformatic studies indicate that approximately 20% of all mammalian mRNAs are probably regulated by mi RNAs. Furthermore, there is strong and rapidly growing evidence suggesting that changes in miRNA regulation is related to malignant transformation and in fact could be a critical event in oncogenic transformation. Little is known about the potential roles of short RNAs in silencing transcription at the level of chromatin in these cells. It is possible that some of the epigenetic changes and genomic instability common of cancers could be directed by RNAi-related pathways. Part of the revolution of RNA interference is the ability to express short hairpin RNAs from vectors to generate siRNAs which silence a specific gene. First, in collaboration with the Jacks and Lees projects, we will develop lentivirus vectors expressing shRNAs in a regulated fashion using tet-activated Pol II transcription. Second, we will use a very sensitive cloning technology for short RNAs to analyze their expression in T-cell populations as they undergo development. The activities of specific miRNAs will be related to known developmental transitions in this defined pathway. Furthermore, the nature of short RNAs in T-cell lymphomas and other tumor cells will be investigated by collaboration with the other projects. The silencing of repetitive sequences by both chromatin modification and DNA methylation is frequently observed in embryonic stem (ES) cells. We will clone short RNAs from ES cells which have been induced to express high levels of RNA from repetitive sequences to investigate the role of short RNAs in gene silencing at the level of transcription. The relationship between the resilencing of repetitive and unique sequences in these ES cells and the sequences of cloned short RNAs will be investigated. Furthermore, the dependence of these processes on Dicer, Argonaute and other RNAi-related genes will be determined. We will also determine the function of a cluster of miRNAs that is exclusively expressed in ES cells and embryonic tissue. Finally, we have found that both the retinoblastoma (Rb) pathway and the RNAi pathway regulate post-mitotic nuclear division in the intestinal epithelium of C. elegans. We will investigate whether related pathways are important for regulation of cell division in mammalian cells.