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）：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进行切割或抑制翻译，mirna被认为在发育、生长、增殖控制和细胞谱系确定中起着关键作用。然而，这类新的调控rna影响恶性肿瘤增殖和分化过程的能力仍有待发现。

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