Targeting miRNA in brain tumors.

靶向脑肿瘤中的 miRNA。

• 批准号: 6962131
• 负责人: Anna M. Krichevsky
• 金额: $ 15.03万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-29 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962131
• 关键词: athymic mouse; biotechnology; cell line; clinical research; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; gene expression; glioblastoma multiforme; human tissue; microRNAs; microarray technology; molecular cloning; molecular oncology; neoplasm /cancer pharmacology; nucleic acid inhibitor; oligonucleotides; small interfering RNA

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are a recently discovered class of small 20-22 nucleotide non-coding RNA molecules that have been shown to regulate target gene expression in various organisms. By targeting the mRNA of protein-coding genes for either cleavage or repression of translation, miRNAs are thought to play critical roles in development, control of growth, proliferation, and cell lineage determination. However, the ability of this new class of regulatory RNAs to influence the processes of proliferation and differentiation in malignancy remains to be uncovered. Using an oligonucleotide array designed to detect the majority of mammalian miRNAs identifies thus far, we measured the expression levels of miRNAs in glioblastomas. This preliminary study identified a cluster of miRNAs that is up-regulated in glioblastomas. Among this cluster one miRNA is markedly elevated. Sequence-specific inhibition of this miRNA with modified antisense oligonucleotides induces apoptosis of glioblastoma cells in culture, suggesting a role for this miRNA in gliomagenesis. Similar regulatory miRNA molecules unique to tumor cells may exist and can serve as prognostic markers and, probably, excellent therapeutic targets for the treatment of high-grade brain tumors. The long-term goal of this proposal is to treat glioblastomas by targeting miRNAs. The immediate goal over the next two years is the development of technologies required for identification and validation of miRNA targets. We will create an oligonucleotide array for the complete profiling of miRNA expression in glioblastomas and characterize molecules expressed exclusively in these tumors. We will then develop ways to suppress these miRNAs in glioblastoma cell cultures and assess the effects on the migratory, apoptotic, and proliferative capacity of the tumor cells. Furthermore, we will test the potential of the miRNA inhibitors in animal models in vivo. Although beyond the scope of this proposal, in the ensuing years we will study downstream mRNA and protein targets that mediate miRNA functions. The results of the experiments proposed here will improve our understanding of biology of brain rumors. Moreover, miRNA targeting technology developed in this research could open the door to novel treatments of glioblastoma.

描述(申请人提供)：microRNAs(MiRNAs)是最近发现的一类小的20-22个核苷酸的非编码RNA分子，已被证明在各种生物体中调节靶基因的表达。通过靶向蛋白质编码基因的mRNA来切割或抑制翻译，miRNAs被认为在发育、控制生长、增殖和细胞谱系决定方面发挥关键作用。然而，这类新的调控RNA在恶性肿瘤中影响增殖和分化过程的能力仍未被发现。 使用一个设计来检测到目前为止识别的大多数哺乳动物miRNAs的寡核苷酸阵列，我们测量了miRNAs在胶质母细胞瘤中的表达水平。这项初步研究确定了一组在胶质母细胞瘤中上调的miRNAs。在这一簇中，有一个miRNA明显升高。序列特异性地用修饰的反义寡核苷酸抑制这种miRNA可以诱导培养的胶质母细胞瘤细胞凋亡，这表明这种miRNA在胶质瘤的发生中发挥了作用。肿瘤细胞特有的类似的调节miRNA分子可能存在，并可作为预后标志，并可能成为治疗高级别脑肿瘤的极佳治疗靶点。这项提议的长期目标是通过靶向miRNAs来治疗胶质母细胞瘤。今后两年的近期目标是开发识别和验证miRNA靶标所需的技术。我们将创建一个寡核苷酸阵列，用于完整地描述胶质母细胞瘤中miRNA的表达，并表征仅在这些肿瘤中表达的分子。然后，我们将开发在胶质母细胞瘤细胞培养中抑制这些miRNAs的方法，并评估对肿瘤细胞迁移、凋亡和增殖能力的影响。此外，我们还将在动物体内模型中测试miRNA抑制剂的潜力。虽然超出了这项建议的范围，但在接下来的几年里，我们将研究介导miRNA功能的下游mRNA和蛋白质靶标。这里提出的实验结果将提高我们对大脑谣言生物学的理解。此外，本研究开发的miRNA靶向技术可能为胶质母细胞瘤的新治疗打开大门。