Investigating the functions of the miR-17~92 family of oncogenic microRNA cluster

致癌microRNA簇miR-17~92家族功能的研究

• 批准号: 8034401
• 负责人: Andrea Ventura
• 金额: $ 38.42万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034401
• 关键词: Acute; Alleles; Animal Model; Applications Grants; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Biological Process; Cells; Development; Family; Functional RNA; Gene Expression; Gene Expression Profiling; Generations; Genes; Goals; Health; Human; Knock-out; Knowledge; Laboratory mice; Lymphomagenesis; Maintenance; Malignant Neoplasms; MicroRNAs; Modeling; Mus; Oncogenic; Pathogenesis; Phyllanthus emblica; Physiological; Plants; Play; Pre-Clinical Model; Property; Public Health; Role; Series; Testing; Therapeutic; Trans-Activators; Tumor Suppressor Genes; Work; base; c-myc Genes; in vivo; insight; loss of function; novel; novel therapeutic intervention; overexpression; paralogous gene; pre-clinical; research study; tumor

DESCRIPTION (provided by applicant): MicroRNAs are small non-coding RNAs that have recently emerged as important modulators of gene expression in metazoans and in plants. In addition to playing important roles in normal development and differentiation, some miRNAs have been shown to act as oncogenes and tumor suppressors. In particular, several lines of evidence indicate that the miR-17~92 cluster includes at least one oncogenic miRNA. Amplification and overexpression of this cluster are frequently observed in a subset of human B-cell lymphomas and in a significant number of other human cancers. The goal of this project is to investigate the biological functions, the physiological targets and the oncogenic properties of this cluster and its two paralogs: miR-106b~25 and miR-106a~363. We propose to use the laboratory mouse as the model organism for these studies and we have already generated mice carrying conditional and constitutive loss-of-function alleles of these three clusters. This application is articulated in three specific aims. In aim 1 we will investigate the functions of miR-17~92 and its two paralogs in mammalian development. The experiments proposed in this aim will allow us to genetically dissect the miR-17~92 cluster and to assign specific biological functions to the six microRNAs that it encodes. In addition they will allow us to determine the extent of functional overlap between miR-17~92 and its two paralogs, miR-106~363 and miR-106b~25. In aim 2, we will investigate the role of miR-17~92 in tumor maintenance in the context of c-Myc induced B cell lymphomas. The rationale for this specific aim is based on the observation that c-Myc is a potent transcriptional transactivator of miR-17~92 and on our own preliminary studies showing that acute deletion of miR-17~92 leads to a dramatic reduction in the proliferation of E5-Myc B-lymphoma cells. The ultimate goal of this aim is to determine the therapeutic potential of pharmacological antagonists of miR-17~92 in a preclinical model of B cell lymphomas. The objective of aim 3 is to identify the set of genes that are physiologic targets of miR-17~92 and to validate their functional relevance in cell-based experiments and in vivo. These goals will be achieved by combining a computation and an experimental approached that takes advantage of the conditional knockout allele of miR- 17~92 that we have recently generated. The work we are proposing will increase our understanding of the biological functions and mechanism of action of this important class of non-coding genes. Of even greater relevance for human health, it will provide insights into the role of miRNAs in the development to human cancer and may pave the way for novel therapeutic approaches based on their pharmacological inhibition.

描述（由申请人提供）：microRNA是小的非编码RNA，最近出现了后生动物和植物中基因表达的重要调节剂。除了在正常发育和分化中起重要作用外，一些miRNA还被证明是癌基因和肿瘤抑制剂。特别是，几条证据表明miR-17〜92簇至少包含一个致癌miRNA。在人类B细胞淋巴瘤和许多其他人类癌症中，经常观察到该簇的扩增和过表达。该项目的目的是研究该集群及其两个旁系同源物的生物学功能，生理靶标和致癌特性：miR-106b〜25和miR-106a〜363。我们建议将实验室小鼠用作这些研究的模型生物，我们已经产生了这三个簇的有条件和本构损失等位基因的小鼠。该应用在三个特定目标中阐明。在AIM 1中，我们将研究miR-17〜92及其两个旁系同源物在哺乳动物发育中的功能。在此目标中提出的实验将使我们能够基因剖析miR-17〜92簇，并将特定的生物学功能分配给其编码的六个microRNA。此外，它们将使我们能够确定miR-17〜92及其两个旁系同源物之间的功能重叠程度，即miR-106〜363和miR-106b〜25。在AIM 2中，我们将在C-MYC诱导的B细胞淋巴瘤的背景下研究miR-17〜92在肿瘤维持中的作用。该特定目的的基本原理是基于观察到的，即C-MYC是miR-17〜92的有效转录式激活因子，并且基于我们自己的初步研究，表明miR-17〜92的急性缺失导致E5-myc B- lymphoma细胞的增殖急剧减少。该目标的最终目标是确定在B细胞淋巴瘤的临床前模型中，miR-17〜92的药理学拮抗剂的治疗潜力。目标3的目的是确定是miR-17〜92的生理靶标的基因集，并在基于细胞的实验和体内验证其功能相关性。这些目标将通过结合计算和实验方法来实现，该计算利用了我们最近生成的mir-17〜92的条件敲除等位基因。我们提出的工作将增加我们对这一重要类别非编码基因的生物学功能和作用机理的理解。它将与人类健康相关，它将提供有关miRNA在人类癌症发展中的作用的见解，并可能基于其药理抑制作用为新型治疗方法铺平道路。