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.

项目负责人：安娜·克里切夫斯基。胶质母细胞瘤(GBM)是成人最常见和最恶性的脑肿瘤，也是 约10%的儿童中枢神经系统肿瘤。尽管疾病管理非常积极，但通常情况下 包括手术、化疗和放射治疗，基底膜是一种致命疾病，中位生存期仅为 12-15个月。因此，迫切需要新的方法和分子靶点来研究GBM。 MicroRNAs(MiRNAs)的发现，这是一种引起转录后转录的小调节RNA分子 基因表达的下调，真正彻底改变了癌症生物学领域。它暗示了一种完全 可能与人类肿瘤的进展和维持有关的新的基因调控层。 我们在过去8年的工作集中在有助于胶质瘤发生的miRNAs上，今天我们已经 越来越多的证据表明，GBM的生长和侵袭性受到miRNAs的密切调控。 重要的是，由GBM释放的微泡(可能代表着 肿瘤及其颅内环境)，含有大量的miRNA调节因子，包括关键的 致癌miRNAs。我们假设这些分子被周围的正常细胞摄取 肿瘤，并对这些细胞的生理有显著影响。MicroRNA介导的基因调控 受体细胞中的表达可能会导致脑细胞中的变革性事件，从而起到保护作用 或者，最终发挥支持肿瘤生长的作用。为了验证这一假设，我们将：1)描述 人和小鼠GBM细胞的细胞内和细胞外/释放的RNA的谱系，以及 构成GBM微环境的正常脑细胞内RNA；2)研究miRNA转移 GBM与正常细胞体外共培养的差异及其对细胞表型的功能影响 3)研究异种GBM模型和移植模型之间是否存在miRNA转移。 活体动物的正常脑细胞。这项拟议的工作有望为 胶质瘤的生物学和更一般的-miRNA介导的不同细胞群之间的串扰 大脑。