Regulation of microRNA processing

描述（由申请人提供）：MicroRNAs代表了一大类非编码rna，它们通过与靶mrna的3'-非翻译区相互作用来调节基因表达。除了作为发育、分化和许多其他基本细胞过程的重要调节因子外，microRNA的表达与癌症和其他慢性疾病的进展有关，这表明调节特定的microRNA可能具有显著的治疗益处。我们的目的是研究前mrna剪接因子调节miRNA前体子集加工的机制。由于我们也发现了抑制RNase III酶Dicer加工致癌miRNA （miR- 21）的肽模拟物，我们也建议研究这类新分子抑制microRNA加工的机制，并进一步开发它们的活性。我们特别提出：1)研究Fox-1家族剪接因子对microRNA加工的调控。我们将探讨Fox-1和Fox-2下调miR-20b表达的结构和生化机制以及生理后果。2)研究一类新的多肽模拟物和已鉴定的工程化RNA结合蛋白抑制microRNA加工的结构和生化机制。3)提高我们发现的肽抑制剂的活性。通过开展该项目，我们将研究内源性rna结合蛋白和外源性抑制剂如何调节microRNA前体的加工。这将为理解microRNA产生的转录后调控提供关键信息，并为抑制致癌microRNA的活性和提高抑制剂的效力提供新方法。

DESCRIPTION (provided by applicant): MicroRNAs represent a large class of non-coding RNAs that regulate gene expression by interacting with the 3'-untranslated region of target mRNAs. In addition to being essential regulators of development, differentiation and many other basic cellular processes, microRNA expression is associated with the progression of cancer and other chronic diseases, suggesting that regulation of specific microRNAs could have significant therapeutic benefits. Our objective is to investigate the mechanism by which pre-mRNA splicing factors regulate processing of a subset of miRNA precursors. Since we have also identified peptide mimetics that inhibit processing of an oncogenic miRNA (miR- 21) by the RNase III enzyme Dicer, we also propose to investigate the mechanism of inhibition of microRNA processing by this new class of molecules and to further develop their activity. We specifically propose to: 1) Study the regulation of microRNA processing by the Fox-1 family of splicing factors. We will investigate the structural and biochemical mechanism of regulation and the physiological consequences of downregulation of miR-20b expression by Fox-1 and Fox-2. 2) Study the structural and biochemical mechanism of inhibition of microRNA processing by a new class of peptide mimetics and by engineered RNA- binding proteins we have identified. 3) Improve the activity of the peptide inhibitors we have discovered. By conducting this project, we will investigate how processing of microRNA precursors is regulated by endogenous RNA-binding proteins and by exogenous inhibitors. This will provide information critical to understand post-transcriptional regulation of microRNA production, and new approach to inhibiting the activity of oncogenic microRNAs and to improve the potency of the inhibitors.