Validation of microRNA Targets in Glioma

胶质瘤中 microRNA 靶点的验证

• 批准号: 8197277
• 负责人: Anna M. Krichevsky
• 金额: $ 35.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197277
• 关键词: Address; Animal Model; Animals; Antisense Oligonucleotides; Apoptosis; Automobile Driving; Binding; Biological; Biology; Brain; Brain Neoplasms; Bromodeoxyuridine; Cell Cycle; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemistry; Cholesterol; Clinical; Code; Data; Development; Diagnosis; Disease; Event; Family; Gene Expression; Gene Expression Regulation; Genes; Genome; Glioblastoma; Glioma; Goals; Growth; Histopathology; Human; Image; Immunohistochemistry; Implant; In Situ Nick-End Labeling; In Vitro; Individual; Induction of Apoptosis; Injection of therapeutic agent; Intracranial Neoplasms; Knowledge; Lead; Link; Luciferases; Maintenance; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Molecular Target; Nude Mice; Oligonucleotides; Oncogenic; Organism; Pathway Analysis; Patients; Phenotype; Physiological; Play; Population; Post-Transcriptional Regulation; Process; Proteins; RNA; Reporter; Role; Sampling; Seeds; Signal Pathway; Small Interfering RNA; Specificity; Staining method; Stains; TIMP3 gene; Testing; Time; Tumor Biology; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; Western Blotting; Work; annexin A5; cancer initiation; caspase-3; combinatorial; comparative; design; gain of function; glioma cell line; in vitro activity; in vivo; inhibitor/antagonist; insight; interest; knock-down; loss of function; mRNA Expression; migration; mouse model; novel; novel therapeutic intervention; public health relevance; research study; synergism; tool; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Malignant brain tumors of glial origin remain today as a serious clinical and scientific problem as ever. Patients with the most malignant glioma, glioblastoma, have an average survival time of less than one year. Like other cancers, gliomas are diseases caused by dysregulated cell proliferation, differentiation, migration and death. However, molecular events that lead to dysregulation of these key processes are not well understood. How gene expression is controlled in tumor formation will be a critical issue in understanding the biology of these tumors. Recently, a novel class of small regulatory molecules, microRNA (miRNA), has been implicated in post-transcriptional regulation of gene expression in a wide range of cancers. A number of miRNAs are aberrantly expressed in gliomas, and some of them may regulate expression of important oncogenes and tumor suppressors. The overall goal of this proposal is to validate miRNAs playing a functional role in human glioma formation and to elucidate intracellular signaling pathways that mediate functions of these miRNAs. To achieve this goal, selected oncogenic miRNAs will be inhibited in glioma cells and effects of these manipulations on in vitro and in vivo parameters of glioma growth will be examined. Since miRNA inhibition may potentially produce various off-target effects, Specific Aim 1 will involve validation of highly specific oligonucleotide inhibitors for the miRNAs of interest. Using these specific tools, we will validate key mRNA targets that mediate miRNA functions in glioma cells. In Specific Aim 2 we will determine effects of the miRNAs on glioma cell viability, proliferation, and apoptosis in vitro. In Specific Aim 3, using ex vivo and in vivo approaches, we will further determine effects of the miRNAs and most potent miRNA combinations on growth and invasion of intracranial glioma tumors in animal models. The proposed work promises to yield significant new insights into the biology of glioma, and more generally - gene expression in cancer, and may validate a novel class of molecular targets for glioma therapy. PUBLIC HEALTH RELEVANCE: Despite very aggressive treatments, survival for patients diagnosed with malignant brain tumor, glioblastoma, has only marginally changed over the past 25 years. There is a critical need for new molecular targets, concepts and approaches to treat this devastating disease. Recently discovered small regulatory RNA molecules, known as microRNAs, regulate molecular events involved in tumor formation in the brain. The proposed work on microRNAs holds promises to advance our understanding of brain tumors and may open the door to novel treatments.

描述（由申请人提供）：神经胶质起源的恶性脑肿瘤至今仍然是一个严重的临床和科学问题。最恶性的胶质瘤——胶质母细胞瘤患者的平均生存时间不到一年。与其他癌症一样，神经胶质瘤是由细胞增殖、分化、迁移和死亡失调引起的疾病。然而，导致这些关键过程失调的分子事件尚不清楚。如何在肿瘤形成过程中控制基因表达将是了解这些肿瘤生物学的关键问题。 最近，一类新型的小调节分子，microRNA (miRNA)，与多种癌症中基因表达的转录后调节有关。许多miRNA在神经胶质瘤中异常表达，其中一些可能调节重要癌基因和抑癌基因的表达。该提案的总体目标是验证 miRNA 在人类神经胶质瘤形成中发挥的功能作用，并阐明介导这些 miRNA 功能的细胞内信号通路。为了实现这一目标，将在神经胶质瘤细胞中抑制选定的致癌 miRNA，并检查这些操作对神经胶质瘤生长的体外和体内参数的影响。由于 miRNA 抑制可能会产生各种脱靶效应，因此特定目标 1 将涉及验证针对感兴趣的 miRNA 的高度特异性寡核苷酸抑制剂。使用这些特定工​​具，我们将验证在神经胶质瘤细胞中介导 miRNA 功能的关键 mRNA 靶点。在具体目标 2 中，我们将确定 miRNA 对体外神经胶质瘤细胞活力、增殖和凋亡的影响。在具体目标 3 中，我们将使用离体和体内方法进一步确定 miRNA 和最有效的 miRNA 组合对动物模型中颅内神经胶质瘤生长和侵袭的影响。拟议的工作有望对神经胶质瘤的生物学以及更广泛的癌症中的基因表达产生重要的新见解，并可能验证神经胶质瘤治疗的一类新型分子靶点。 公共卫生相关性：尽管采取了非常积极的治疗，但诊断为恶性脑肿瘤、胶质母细胞瘤的患者的生存率在过去 25 年中仅略有变化。迫切需要新的分子靶点、概念和方法来治疗这种毁灭性疾病。最近发现的小调节 RNA 分子（称为 microRNA）可调节与大脑肿瘤形成有关的分子事件。拟议的 microRNA 工作有望增进我们对脑肿瘤的理解，并可能为新的治疗方法打开大门。