miR-155 and RUNX function in neurofibroma tumorigenesis and therapy

miR-155 和 RUNX 在神经纤维瘤发生和治疗中的作用

• 批准号: 9151888
• 负责人: Jianqiang Wu
• 金额: $ 34.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151888
• 关键词: Affect; Apoptosis; Benign; Biodistribution; Biological Assay; Biology; Cell Proliferation; Cells; Chemicals; Clinical; Clinical Trials; Core-Binding Factor; Data; Disease; Drug Monitoring; Embryo; Gene Family; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Goals; Growth; In Vitro; Individual; Inherited; Knock-out; Language; Lead; Link; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Measurement; Methods; MicroRNAs; Modeling; Molecular; Mus; Mutation; NF1 gene; Neurofibromatosis 1; Oncogenes; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Peptide Nucleic Acids; Pharmaceutical Preparations; Phase II Clinical Trials; Prevention; Preventive Intervention; Principal Investigator; Recurrence; Research Design; Role; Schwann Cells; Signal Pathway; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transcription Factor AP-1; Treatment Efficacy; Tumor Suppressor Proteins; Work; activating transcription factor 4; analog; base; cell growth; cohort; effective therapy; experience; in vivo; inhibitor/antagonist; loss of function; mouse model; nanoparticle; neurofibroma; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; progenitor; programs; public health relevance; targeted treatment; transcription factor; tumor; tumorigenesis

Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang Project summary Using technical language, briefly describe the research design and rationale for achieving the stated goals Neurofibromatosis type 1 (NF1) patients develop vary number of benign Schwann cell tumors called neurofibromas for which there is no effective therapy available except surgery. New therapeutic strategies and new targets are urgently needed. We showed that: a) targeted genetic deletion of Runx1 & 3 simultaneously, or pharmacological inhibition of Runx function with a Runx1/Cbfβ interaction inhibitor, Ro5-3335, inhibits mouse neurofibroma cell proliferation and induces cell apoptosis in vivo. b) five ERK-dependent and 6 ERK- independent miRs are deregulated >2 folds in mouse neurofibromas compared to normal mouse Schwann cells, c) miR-155 is regulated by ERK/AP-1. d) anti-miR-155 peptide nucleic acids (PNAs) inhibit mouse neurofibroma Schwann cell progenitor growth. e). Whole body knock out of miR-155 partially delays neurofibroma formation. We hypothesize that Runx1 & Runx3 and miR-155 are involved in neurofibroma formation, and inhibition of Runx/Cbfβ and/or miR-155 expression will provide new therapies for neurofibroma. We plan to test this hypothesis by pursuing the following two specific aims using both genetically engineered mouse models and chemical/pharmacological inhibitors. In Aim 1, we will genetically delete Runx1 & Runx3 simultaneously in Schwann cells and Schwann cell precursors by Cre-Loxp technique or inactivate Runx genes by inhibition of Runx/Cbfβ interaction using a pharmacological inhibitor to determine Runx function in neurofibroma formation. We will also determine the mechanism(s) by which Runx1 & Runx3 regulate neurofibroma cell growth in vitro. In Aim 2, we will inactivate ERK-dependent miR-155 in vivo by genetically mutation or chemically modified anti-miR-155 peptide nucleic acids (PNAs) that is delivered by a high efficacious nanoparticle system to determine the role of miR-155 in neurofibroma formation. We will dissect miR-155 pathways by determining how loss of Nf1 upregulates miR-155 and how miR-155 contributes to neurofibroma cell growth. We will determine if there is a causative link between miR-155 and Runx1 & Runx3. Overall, this proposal will provide mechanistic evidence of Runx1/3 and miR-155 function as oncogenes on neurofibroma formation and provide pre-clinical rationale for clinical trials.

主要研究者/项目负责人（末、首、中）：吴建强 使用技术语言，简要描述研究设计和实现既定目标的基本原理 神经纤维瘤病1型（NF 1）患者发展不同数量的良性雪旺细胞瘤，称为 神经纤维瘤，除了手术外没有有效的治疗方法。新的治疗策略和 迫切需要新的目标。我们发现：a）同时靶向基因缺失Runx 1和3， 或用Runx 1/Cbfβ相互作用抑制剂Ro 5 -3335药理学抑制Runx功能， 小鼠神经纤维瘤细胞增殖并诱导细胞凋亡。B）5种ERK依赖性和6种ERK- 与正常小鼠雪旺氏细胞瘤相比，小鼠神经纤维瘤中的独立miR失调>2倍 c）miR-155受ERK/AP-1调节。d）抗-miR-155肽核酸（PNA）抑制小鼠 神经纤维瘤雪旺氏细胞祖细胞生长。e）。miR-155的全身敲除部分延迟 神经纤维瘤形成。我们假设Runx 1和Runx 3以及miR-155参与了神经纤维瘤的形成 因此，通过抑制Runx/Cbfβ和/或miR-155的表达，将为神经纤维瘤提供新的治疗方法。 我们计划通过以下两个具体目标来验证这一假设， 小鼠模型和化学/药理学抑制剂。在目标1中，我们将从基因上删除Runx 1和Runx 3 同时在雪旺细胞和雪旺细胞前体细胞中通过Cre-Loxp技术或RT-PCR Runx基因 通过使用药理学抑制剂抑制Runx/Cbfβ相互作用，以确定 神经纤维瘤形成。我们还将确定Runx 1和Runx 3调节的机制。 体外神经纤维瘤细胞生长。在目标2中，我们将通过基因工程在体内表达ERK依赖的miR-155， 突变或化学修饰的抗miR-155肽核酸（PNA），其通过高表达载体递送。 有效的纳米颗粒系统，以确定miR-155在神经纤维瘤形成中的作用。我们将解剖 通过确定Nf 1的缺失如何上调miR-155以及miR-155如何促进miR-155通路， 神经纤维瘤细胞生长。我们将确定miR-155与Runx 1和Runx 3之间是否存在因果关系。 总的来说，这项提议将提供Runx 1/3和miR-155作为癌基因在乳腺癌中发挥作用的机制证据。 神经纤维瘤的形成，并为临床试验提供临床前的基本原理。