Master Regulatory MicroRNAs in Glioblastoma

掌握胶质母细胞瘤中的调节性 MicroRNA

• 批准号: 9395328
• 负责人: Roger Abounader
• 金额: $ 46.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395328
• 关键词: 3' 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

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）是最常见和最致命的原发性恶性脑肿瘤。尽管最 结合手术、放疗和化疗的高级治疗，GBM与 平均寿命只有15个月。靶向分子治疗可以说是最有效的治疗方法之一。 实现更有效的未来GBM疗法的有前途的方法。这样一个国家面临的一个重大挑战是， 一种方法是在任何给定的单个肿瘤中同时解除多个分子的调节，如 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， 令人惊讶的是，分子单一疗法未能实现GBM临床治疗的显著改善， 结果。一些证据表明，同时靶向多种失调分子， 和途径来实现更好的治疗。基于初步证据，我们假设 存在"主调节微RNA"（miRNAs），其同时调节多个 GBM中的失调分子。这个应用程序的目标是发现，调查， 在治疗上利用这些miRNAs。我们认为，研究这些资料将提供关于 GBM中基因表达（去）调节的机制以及恢复或抑制它们可以被利用 治疗我们提出三个具体目标。在目标1中，我们将使用一种新的筛选方法，PAR-CLIP， 与smRNA-seq和TCGA基因表达数据分析相结合，以揭示全局miRNA靶点， 鉴定同时靶向和调节细胞凋亡的单个miRNA（称为主调节miRNA）。 GBM中最大数量的失调分子。在目标2中，我们将研究 这些主要调控miRNAs的作用，并验证其在人类GBM中的表达和靶点 标本在目标3中，我们将测试miRNA作为GBM中的新实验治疗剂或靶标。 因此，我们将开发和使用新的潜在临床适用的局部和全身给药制剂， 包括脑穿透纳米颗粒（BPN）、对流增强递送（CED）和聚焦的方法 微泡超声（FUS-MB）。成功完成拟议的研究将建立 GBM中miRNA靶点的第一个概要，产生关于基因（去）调节的新知识 miRNAs的表达及其对GBM恶性肿瘤的影响，并开发新的技术， 在GBM治疗中开发新型主调节miRNA。