Cancer is a major disease burden and one hope of changing this is to develop new treatments through abetter understanding of the disease. Recent discoveries concerning the activities of short RNAs in mammalsmay provide both new insights and new treatments of cancer. Cancer is a disease of gene dysregulationcaused by mutations and epigenetic changes. Short RNAs are now known to regulate genes at the levels ofmRNA degradation, primarily by siRNAs, mRNA translation, primarily by microRNAs, and mRNAtranscription, primarily by repeat-associated short interfering RNAs (rasiRNAs). Recent results frombioinformatic studies indicate that approximately 20% of all mammalian mRNAs are probably regulated bymi RNAs. Furthermore, there is strong and rapidly growing evidence suggesting that changes in miRNAregulation is related to malignant transformation and in fact could be a critical event in oncogenictransformation. Little is known about the potential roles of short RNAs in silencing transcription at the levelof chromatin in these cells. It is possible that some of the epigenetic changes and genomic instabilitycommon of cancers could be directed by RNAi-related pathways. Part of the revolution of RNA interferenceis 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 shRNAsin a regulated fashion using tet-activated Pol II transcription. Second, we will use a very sensitive cloningtechnology 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 bycollaboration with the other projects. The silencing of repetitive sequences by both chromatin modificationand DNA methylation is frequently observed in embryonic stem (ES) cells. We will clone short RNAs fromES cells which have been induced to express high levels of RNA from repetitive sequences to investigatethe role of short RNAs in gene silencing at the level of transcription. The relationship between theresilencing of repetitive and unique sequences in these ES cells and the sequences of cloned short RNAswill be investigated. Furthermore, the dependence of these processes on Dicer, Argonaute and other RNAi-relatedgenes will be determined. We will also determine the function of a cluster of miRNAs that isexclusively 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 inmammalian cells.
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