Master Regulatory MicroRNAs in Glioblastoma

掌握胶质母细胞瘤中的调节性 MicroRNA

• 批准号: 10212339
• 负责人: Roger Abounader
• 金额: $ 44.79万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212339
• 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.

抽象的 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、放疗和化疗的先进治疗，GBM 与 平均预期寿命只有约15个月。靶向分子疗法可以说是最有效的疗法之一 未来实现更有效的 GBM 治疗的有希望的方法。这样一个面临的重大挑战 方法是在任何给定的单一肿瘤中同时解除对多个分子的管制，如以下所证明的 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，单一分子疗法未能在 GBM 临床上取得显着改善 结果。多项证据表明，同时靶向多个解除管制的分子 并需要途径来实现更好的治疗。根据初步证据，我们假设 存在同时调节多个的“主调控 microRNA”（miRNA） GBM 中的分子失调。此应用程序的目标是发现、调查和 治疗性地利用此类 miRNA。我们相信，研究它们将为我们提供新的信息。 GBM 中基因表达（去）调节的机制以及可以利用恢复或抑制它们的机制 用于治疗。我们提出三个具体目标。在目标 1 中，我们将使用一种新颖的筛选方法 PAR-CLIP， 结合 smRNA-seq 和 TCGA 基因表达数据分析来发现全局 miRNA 靶标 识别同时靶向和调节的单个 miRNA（指定的主调控 miRNA） GBM 中失调分子的数量最多。在目标2中，我们将研究 这些主调控 miRNA 的作用并验证它们在人类 GBM 中的表达和靶标 标本。在目标 3 中，我们将测试 miRNA 作为 GBM 的新型实验治疗剂或靶点。 因此，我们将开发和使用新型的潜在临床适用的局部和全身递送剂， 方法包括脑穿透纳米粒子（BPN）、对流增强递送（CED）和聚焦 微泡超声 (FUS-MB)。成功完成拟议的研究将建立 GBM 中第一个 miRNA 靶标纲要，产生有关基因（去）调控的新知识 miRNA 的表达及其对 GBM 恶性肿瘤的影响，并开发新技术 GBM 治疗中新型主调控 miRNA 的开发。