Novel Bi-functional Inhibitors Blocking OncomiR Biogenesis

 描述(由申请人提供)：本提案的目标是开发一种新型的选择性miRNA调节剂，阻止肿瘤生长因子受体的成熟。MicroRNAs(MiRNAs)调节多种生物过程。MicroRNAs调节失调(MiRNAs)已成为肿瘤形成和发展的新机制之一。越来越多的证据表明，某些miRNAs影响细胞转化、癌变和转移，并作为癌基因(致癌miRNAs或oncomiRs)发挥作用。了解肿瘤抑制因子在癌症中的作用将有助于开发新的癌症治疗方法。此外，肿瘤相关基因的直接治疗干预已成为治疗癌症的一个有前途的新方向。无论是出于研究还是治疗目的，控制癌链球蛋白水平的方法都是非常可取的。目前用于这种目的的方法通常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策略来调节miRNA。我们将开发一类新的双功能miRNA调节剂，由独立和专门的“前miRNA识别单元”和“Diller抑制单元”组成，以靶向独特的前miRNAs，并通过抑制Diller酶活性来阻止其加工生成成熟的miRNAs。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。我们将合成针对miRNA-21(miR-21)和其他肿瘤抑制因子的双功能调节剂，并检测它们的抑制活性。目的2：检测双功能miRNA调节剂在细胞内的活性和特异性。我们将优化哺乳动物细胞对该调节剂的摄取。该调节器的细胞活动和偏离目标的影响将是 以单元格计算。这项工作将为一种新的oncomiR调控策略奠定技术基础。这项独特的技术将解决目前miRNA调控方法中遇到的主要障碍，并增强分析肿瘤相关基因在癌症生物学中的作用的能力。这将大大促进我们对肿瘤抑制因子在癌症中所起作用的了解，并将直接基于双模块调节器或从对这项新技术揭示的肿瘤抑制因子功能的理解中发展出新的癌症治疗方法。

 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.