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Master Regulatory MicroRNAs in Glioblastoma

掌握胶质母细胞瘤中的调节性 MicroRNA

基本信息

批准号：
10411430
负责人：
Roger Abounader
金额：
$ 6.79万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-09 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411430
关键词：
3&apos Untranslated Regions Binding Bioinformatics Brain Cells Clinical Collaborations Complex Convection Data Data Analyses Databases Development Focused Ultrasound Future Gene Expression Gene Expression Regulation Genes Glioblastoma Goals High-Throughput Nucleotide Sequencing Human Immunoprecipitation Investigational Therapies Knowledge Lead Life Expectancy Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Messenger RNA MicroRNAs Microbubbles Molecular Nucleic Acids Oncogenic Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Price Proteins Publishing RNA Radiation therapy Regulation Research Resolution Role Specimen Testing The Cancer Genome Atlas Therapeutic Therapeutic Agents Therapeutic Studies Time Toxic effect Translations Universities Untranslated RNA Xenograft procedure base chemotherapy clinical application conventional therapy crosslink effective therapy experimental study improved mRNA Transcript Degradation molecular targeted therapies nanomedicine nanoparticle new technology novel novel strategies screening therapeutic miRNA therapeutic target transcriptome tumor

项目摘要

ABSTRACT Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Despite the most advanced treatment with combinations of surgery, radiotherapy and chemotherapy, GBM is associated with a median life expectancy of only ~15 months. Targeted molecular therapies are arguably one of the most promising approaches to achieving more effective future GBM therapies. A major challenge facing such an approach is the simultaneous deregulation of multiple molecules in any given single tumor, as demonstrated by The Cancer Genome Atlas (TCGA) and other published research. Because of this co-deregulation, it is not surprising that molecular monotherapies have failed to achieve significant improvements in GBM clinical outcomes. Several lines of evidence suggest that the simultaneous targeting of multiple deregulated molecules and pathways is required to achieve better therapies. Based on preliminary evidence, we hypothesize that there exist “master regulatory microRNAs” (miRNAs) that simultaneously regulate multiple deregulated molecules in GBM. The goal of this application is to discover, investigate, and therapeutically exploit such miRNAs. We believe that studying them will provide new information on the mechanisms of gene expression (de)regulation in GBM and that restoring or inhibiting them can be exploited for therapy. We propose three specific aims. In aim 1, we will use a novel screening approach, PAR-CLIP, in combination with smRNA-seq and TCGA gene expression data analysis to uncover global miRNA targets and identify single miRNAs (designated master regulatory miRNAs) that simultaneously target and regulate the largest number of deregulated molecules in GBM. In aim 2, we will investigate the functions and modes of action of these master regulatory miRNAs and validate their expressions and targets in human GBM specimens. In aim 3, we will test miRNAs as novel experimental therapeutic agents or targets in GBM. Thereby, we will develop and use novel potentially clinically applicable local and systemic delivery agents and approaches including brain penetrating nanoparticles (BPN), convection-enhanced delivery (CED) and focused ultrasound with microbubbles (FUS-MB). Successful completion of the proposed studies would establish the first compendium of miRNA targets in GBM, generate new knowledge on the (de)regulation of gene expression by miRNAs and their effects on GBM malignancy, and develop novel technologies for the exploitation of novel master regulatory miRNAs in GBM therapy.

摘要胶质母细胞瘤(GBM)是最常见、最致命的原发脑肿瘤。尽管世界上结合手术、放疗和化疗的晚期治疗，GBM与平均预期寿命只有15个月左右。靶向分子疗法可以说是最具争议性的未来实现更有效的GBM疗法的前景看好的方法。面临着这样一个重大挑战方法是在任何给定的单个肿瘤中同时解除对多个分子的调控，如下所示癌症基因组图谱(TCGA)和其他已发表的研究。由于这种共同放松管制，它并不是令人惊讶的是，分子单一疗法未能在GBM临床上取得显著改善结果。几条证据表明，同时靶向多个放松管制的分子而实现更好的治疗需要多种途径。根据初步证据，我们假设存在同时调节多个 GBM中未受调控的分子。此应用程序的目标是发现、调查和在治疗上利用这种miRNA。我们相信，对它们的研究将提供关于基底膜的基因表达(去调节)机制以及恢复或抑制它们的机制可以被利用接受治疗。我们提出了三个具体目标。在目标1中，我们将使用一种新的筛选方法，PAR-CLIP，在结合smRNA-seq和TCGA基因表达数据分析，揭示全球miRNA靶点和识别单个miRNAs(指定为主调控miRNAs)，同时靶向和调节 GBM中非调控分子的数量最多。在目标2中，我们将研究网络的功能和模式这些主要调控miRNAs的作用及其在人GBM中的表达和靶点验证标本。在目标3中，我们将在GBM中测试miRNAs作为新的实验性治疗剂或靶点。因此，我们将开发和使用新的具有临床应用潜力的局部和全身给药制剂，并方法包括脑穿透纳米粒(BPN)、对流增强释放(CED)和聚焦微泡超声(FUS-MB)。成功完成拟议的研究将确立第一个GBM中miRNA靶标的概要，产生了关于基因(去)调控的新知识 MiRNAs的表达及其对GBM恶性的影响，并开发新的技术新型主控miRNAs在GBM治疗中的开发。