Targeting miRNA in brain tumors.

靶向脑肿瘤中的 miRNA。

• 批准号: 7140159
• 负责人: Anna M. Krichevsky
• 金额: $ 14.7万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140159
• 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（由申请人提供）：MicroRNA（miRNA）是最近发现的一类20-22个核苷酸的小非编码RNA分子，已被证明可以调节多种生物体中的靶基因表达。 通过靶向蛋白质编码基因的 mRNA 进行裂解或翻译抑制，miRNA 被认为在发育、生长控制、增殖和细胞谱系决定中发挥着关键作用。 然而，这种新型调节 RNA 影响恶性肿瘤增殖和分化过程的能力仍有待揭示。 使用设计用于检测迄今为止鉴定的大多数哺乳动物 miRNA 的寡核苷酸阵列，我们测量了胶质母细胞瘤中 miRNA 的表达水平。 这项初步研究鉴定了一组在胶质母细胞瘤中表达上调的 miRNA。 在该簇中，有一个 miRNA 显着升高。 用修饰的反义寡核苷酸对该 miRNA 进行序列特异性抑制，可诱导培养物中胶质母细胞瘤细胞的凋亡，表明该 miRNA 在胶质瘤发生中的作用。 肿瘤细胞特有的类似调节 miRNA 分子可能存在，并且可以作为预后标记，并且可能是治疗高级脑肿瘤的极好治疗靶点。 该提案的长期目标是通过靶向 miRNA 来治疗胶质母细胞瘤。 未来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，用于完整分析胶质母细胞瘤中的 miRNA 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物中抑制这些 miRNA 的方法，并评估其对肿瘤细胞迁移、凋亡和增殖能力的影响。 此外，我们将在体内动物模型中测试 miRNA 抑制剂的潜力。 尽管超出了本提案的范围，但在接下来的几年中，我们将研究介导 miRNA 功能的下游 mRNA 和蛋白质靶点。 这里提出的实验结果将提高我们对大脑生物学的理解。 此外，本研究中开发的 miRNA 靶向技术可以为胶质母细胞瘤的新疗法打开大门。

项目成果

MicroRNA profiling: from dark matter to white matter, or identifying new players in neurobiology.

• DOI: 10.1100/tsw.2007.201
• 发表时间: 2007-11-02
• 期刊: TheScientificWorldJournal
• 作者: Krichevsky AM