Regulation of microRNA processing

microRNA 加工的调控

• 批准号: 9132816
• 负责人: Gabriele Varani
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132816
• 关键词: 3' Untranslated Regions; Affect; Alternative Splicing; Alzheimer' s Disease; Binding; Binding Sites; Biochemical; Biogenesis; Biological Assay; Biological Process; Cell Death; Cell Extracts; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cholesterol; Chronic Disease; Cleaved cell; Complex; Cyclic Peptides; Cytoplasm; Development; Dicer Enzyme; Disease Progression; Down-Regulation; Engineering; Family; Foxes; Gene Expression; Gene Targeting; Genes; Genetic; Health; Human; In Vitro; Individual; Lead; Lipoproteins; Malignant Neoplasms; Messenger RNA; MicroRNAs; Nucleotides; Oligonucleotides; Oncogenic; Peptides; Physiological; Plasma; Post-Transcriptional Regulation; Process; Production; Protein Engineering; Protein Family; Proteins; RNA Binding; RNA Precursors; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Regulation; Ribonuclease III; Therapeutic; Time; Transcript; Untranslated RNA; analog; base; cancer cell; exportin 5; human disease; improved; in vivo; inhibitor/antagonist; insulin sensitivity; knock-down; mRNA Precursor; mRNA Stability; malignant breast neoplasm; novel strategies; novel therapeutics; overexpression; peptidomimetics; pre-miRNA; pri-miRNA; stem; tumor progression

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.

描述(申请人提供)：microRNAs代表一大类非编码RNAs，它通过与靶mRNAs的3‘-非翻译区相互作用来调节基因表达。除了是发育、分化和许多其他基本细胞过程的基本调节外，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microRNAs可能具有显著的治疗益处。我们的目标是研究前mRNA剪接因子调节miRNA前体子集的加工的机制。由于我们还发现了抑制RNaseIII酶Disher对致癌miRNA(miR-21)加工的多肽模拟物，因此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。我们具体建议：1)研究Fox-1剪接因子家族对microRNA加工的调节。我们将研究Fox-1和Fox-2下调miR-20b表达的结构和生化机制以及下调miR-20b表达的生理后果。2)研究了一类新的多肽模拟物和我们鉴定的工程RNA结合蛋白抑制microRNA加工的结构和生化机制。3)提高我们已发现的多肽抑制剂的活性。通过这个项目，我们将研究内源RNA结合蛋白和外源抑制物如何调节microRNA前体的加工。这将为理解microRNA生产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的途径。