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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

基本信息

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
项目类别：
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

项目摘要

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：Anna Krichevsky。胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，也是造成恶性肿瘤的主要原因