Novel Bi-functional Inhibitors Blocking OncomiR Biogenesis

阻断 OncomiR 生物发生的新型双功能抑制剂

• 批准号: 9036024
• 负责人: Fu-Sen Liang
• 金额: $ 18.51万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036024
• 关键词: Address; Adverse effects; Affect; Affinity; Antisense Oligonucleotides; Binding; Biogenesis; Biological Assay; Biological Process; Cancer Biology; Cell physiology; Cells; Development; Dicer Enzyme; Foundations; Generations; Goals; In Vitro; Knowledge; Lead; Link; Malignant Neoplasms; Mammalian Cell; Messenger RNA; Methods; MicroRNAs; Neoplasm Metastasis; Northern Blotting; Oncogenes; Oncogenic; Pathogenesis; Play; Process; Proteins; RNA; Regulation; Research; Role; Specificity; Technology; Testing; Therapeutic Human Experimentation; Therapeutic Intervention; Untranslated RNA; Western Blotting; Work; base; cancer therapy; cancer type; carcinogenesis; design; improved; inhibitor/antagonist; interest; metaplastic cell transformation; new technology; next generation; novel; novel strategies; novel therapeutics; public health relevance; research and development; ribosome profiling; transcriptome sequencing; uptake

 DESCRIPTION (provided by applicant): The objective of this proposal is to develop a new class of selective miRNA regulators that blocks the maturation of oncomiRs. MicroRNAs (miRNAs) regulate diverse biological processes. Dysregulation of microRNAs (miRNAs) has become one of the emerging mechanisms contributes to cancer formation and progression. Increasing evidences suggest that certain miRNAs affect cellular transformation, carcinogenesis and metastasis, and act as oncogenes (oncogenic miRNAs or oncomiRs). Understanding the roles of oncomiRs in cancer will lead to the development of new cancer therapies. Besides, direct therapeutic intervention of oncomiRs has become a promising new direction for treating cancer. For both research and therapeutic purposes, methods allowing the control of oncomiR levels are highly desirable. Current methods for such purposes generally suffer from the off-target inhibition. To address this critical issue, we propose a novel strategy to regulate miRNA. We will develop a new class of bi-functional miRNA regulators consisting of independent and specialized "pre-miRNA recognition unit" and "Dicer inhibition unit" to target unique pre- miRNAs and block their processing to generate mature miRNAs by inhibiting Dicer enzymatic activity. The following Aims will accomplish our goal of establishing this new strategy: Aim 1. Synthesize and test bi- functional miRNA regulators. We will synthesize bi-functional regulators for miRNA-21 (miR-21) and other oncomiRs and test their inhibitory activity. Aim 2: Test the activity and specificity of the bi-functional miRNA regulator in cells. We will optimize cellular uptake of the regulator in mammalian cells. The cellular activity and off-target effects of the regulator will be evaluated in cells. This work will establish the technical foundation of a novel oncomiR regulation strategy. This unique technology will address the major obstacle encountered in current miRNA regulating methods and enhance the capability to dissect the roles of oncomiRs in cancer biology. It will significantly contribute to the advancement in our knowledge of the role played by oncomiRs in cancer and will result in the development of novel cancer therapies either directly based on the bi- modular regulators or evolved from the understanding of oncomiR functions unveiled by this new technology.

 描述（由申请人提供）：本提案的目的是开发一类新型选择性 miRNA 调节剂，阻止 oncomiR 的成熟。 MicroRNA (miRNA) 调节多种生物过程。 microRNA (miRNA) 的失调已成为促进癌症形成和进展的新兴机制之一。越来越多的证据表明某些 miRNA 影响细胞转化、癌变和转移，并充当癌基因（致癌 miRNA 或 oncomiR）。了解 oncomiR 在癌症中的作用将有助于开发新的癌症疗法。此外，oncomiRs的直接治疗干预已成为治疗癌症的一个有前景的新方向。出于研究和治疗目的，非常需要能够控制 oncomiR 水平的方法。目前用于此类目的的方法通常会受到脱靶抑制的影响。为了解决这个关键问题，我们提出了一种新的调控 miRNA 的策略。我们将开发一类新的双功能 miRNA 调节因子，由独立且专门的“pre-miRNA 识别单元”和“Dicer 抑制单元”组成，以靶向独特的 pre-miRNA，并通过抑制 Dicer 酶活性来阻止其加工生成成熟 miRNA。以下目标将实现我们建立这一新策略的目标： 目标 1. 合成和测试双功能 miRNA 调节剂。我们将合成 miRNA-21 (miR-21) 和其他 oncomiR 的双功能调节剂并测试它们的抑制活性。目标 2：测试细胞中双功能 miRNA 调节因子的活性和特异性。我们将优化哺乳动物细胞中调节剂的细胞摄取。调节器的细胞活性和脱靶效应将是 在细胞中进行评估。这项工作将为新型 oncomiR 调控策略奠定技术基础。这项独特的技术将解决当前 miRNA 调节方法中遇到的主要障碍，并增强剖析 oncomiR 在癌症生物学中的作用的能力。它将极大地促进我们对 oncomiR 在癌症中所发挥作用的认识的进步，并将导致直接基于双模块调节剂或从这项新技术揭示的 oncomiR 功能的理解中发展出来的新型癌症疗法的发展。