Transfer of microRNA regulators from glioblastoma to brain microenvironment

microRNA调节剂从胶质母细胞瘤转移到脑微环境

• 批准号: 8590465
• 负责人: XANDRA OWENS BREAKEFIELD
• 金额: $ 41.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590465
• 关键词: Accounting; Adult; Affect; Animals; Apoptosis; Apoptotic; Biology; Brain; Cancer Biology; Cell Cycle; Cell Death; Cell physiology; Cells; Childhood; Childhood Central Nervous System Neoplasm; Coculture Techniques; Communication; Development; Disease; Disease Management; Environment; Event; Gene Expression Regulation; Genes; Glioblastoma; Glioma; Gliomagenesis; Growth; High Density Lipoproteins; Human; In Vitro; Invaded; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; MicroRNAs; Modeling; Molecular Target; Mus; Neoplasms; Normal Cell; Oncogenic; Operative Surgical Procedures; Patients; Phenotype; Physiology; Population; Primary Brain Neoplasms; RNA; Radiation therapy; Small RNA; Stimulus; Time; Tumor Suppressor Genes; Vesicle; Work; Xenograft procedure; brain cell; chemotherapy; extracellular; gene repression; in vivo; insight; neoplastic cell; novel; novel strategies; particle; prevent; protein complex; tumor; tumor growth

Prject Leader: Anna Krichevsky. Glioblastoma (GBM) is the most common and malignant brain tumor in adults and also accounts for approximately 10% of pediatric CNS tumors. Despite very aggressive disease management, that usually includes surgery, chemotherapy and radiotherapy, GBM is a fatal disease with median survival time of only 12-15 months. Novel approaches and molecular targets for GBM are, therefore, urgently needed. The discovery of microRNAs (miRNAs), small regulatory RNA molecules that cause post-transcriptional down-regulation of gene expression, truly revolutionized the field of cancer biology. It suggested an entirely new layer of gene regulation that might be involved in progression and maintenance of human neoplasia. Our work over the past 8 years focused on miRNAs that contribute to gliomagenesis, and today we have mounting evidence indicating that GBM growth and invasiveness are closely regulated by miRNAs. Importantly, microvesicles released by GBM (which may represent a means of communication between the tumor and its intracranial environment), contain large amounts of miRNA regulators, including the key oncogenic miRNAs. We hypothesize that these molecules are taken-up by normal cells surrounding the tumor, and have significant effects on the physiology of these cells. MicroRNA-mediated regulation of gene expression in the recipient cells may lead to transformative events in the brain cells, serving either protective or, ultimately, tumor growth-supportive function. To validate this hypothesis, we will: 1) characterize the repertoire of intracellular versus extracellular/released RNA in human and mouse GBM cells, and intracellular RNA in normal brain cells that constitute GBM microenvironment; 2) investigate miRNA transfer between GBM and normal cells in co-cultures in vitro, and its functional effects on the phenotypes ofthe recipient cells, and 3) investigate whether miRNA transfer exists between the xenograft GBM models and normal brain cells in animals in vivo. The proposed work promises to yield significant new insights into the biology of glioma and more generally- miRNA-mediated crosstalk between different cell populations in the brain.

主持人：安娜·克里切夫斯基（Anna Krichevsky）。胶质母细胞瘤（GBM）是成年人中最常见和最恶性的脑肿瘤，也解释了 大约10％的小儿CNS肿瘤。尽管疾病管理非常侵略性，但通常 包括手术，化学疗法和放疗，GBM是一种致命疾病，中位生存时间为 12-15个月。因此，迫切需要GBM的新方法和分子靶标。 发现microRNA（miRNA），小的调节RNA分子，引起转录后 基因表达的下调真正彻底改变了癌症生物学领域。它完全建议 可能参与人类肿瘤的进展和维持的基因调节的新层。 在过去的8年中，我们的工作集中在有助于神经胶质作用的miRNA上，今天我们已经有了 越来越多的证据表明，GBM的生长和侵入性受miRNA密切调节。 重要的是，GBM发布的微泡（这可能代表 肿瘤及其颅内环境），包含大量miRNA调节剂，包括钥匙 致癌miRNA。我们假设这些分子被周围的正常细胞所吸收 肿瘤，对这些细胞的生理学有重大影响。 microRNA介导的基因调节 在受体细胞中的表达可能导致脑细胞中的变换事件，可提供任何保护性 或者，最终是肿瘤生长支持功能。为了验证这一假设，我们将：1）表征 在人和小鼠GBM细胞中细胞内与细胞外/释放的RNA的曲目，以及 构成GBM微环境的正常脑细胞中细胞内RNA； 2）研究miRNA转移 在体外共培养中GBM和正常细胞之间，其功能对表型的作用 受体细胞和3）研究异种移植GBM模型之间是否存在miRNA转移和 体内动物中的正常脑细胞。拟议的工作承诺将对 神经胶质瘤的生物学和更普遍的miRNA介导的在不同细胞种群之间的串扰 脑。