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Investigating the functions of the miR-17~92 family of oncogenic microRNA clusters

研究致癌 microRNA 簇的 miR-17~92 家族的功能

基本信息

批准号：
9247341
负责人：
Andrea Ventura
金额：
$ 38.57万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247341
关键词：
Acute Affect Alleles Apoptosis Applications Grants B-Cell Lymphomas Binding Biochemical Biological Process Cells Chimeric Proteins Code Collaborations Complex Core Grant Development Disease Dissection Employee Strikes Family Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Germ-Line Mutation Goals Grant Health High-Throughput Nucleotide Sequencing Homeostasis Human Impairment Individual Investigation Lead Length Letters Link Lymphoma MYC gene Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Mediating Messenger RNA Methods MicroRNAs Molecular Mouse Strains Mus Mutation Nucleotides Oncogenes Oncogenic Pathogenesis Pattern Pharmacology Physiological Plant Resins Play Pre-Clinical Model Property Proteins RNA interference screen Regulation Regulator Genes Research Proposals Resistance Role Series Syndrome Technology Testing Therapeutic Tissues Toxic effect Translational Repression Treatment Efficacy Tumor Suppressor Proteins United States National Institutes of Health Untranslated RNA Work base cancer initiation design experimental study haloalkane human cancer mouse model in vivo inhibitor/antagonist innovation mouse model novel novel therapeutics overexpression skeletogenesis targeted delivery transcription factor tumor initiation tumor microenvironment tumor progression tumorigenesis virtual

项目摘要

ABSTRACT MicroRNAs (miRNAs) are small non-coding RNAs approximately 21 nucleotides in length that regulate gene expression at the post-transcriptional level by inducing mRNA destabilization and translational inhibition of target mRNAs. In humans, more than 2000 miRNAs have been identified and are thought to control a variety of biological processes development and cancer. The goal of this competitive renewal application is to continue our investigation of the biological functions and the oncogenic properties of the polycistronic miR-17~92 miRNA cluster, also known as Oncomir1. The miR- 17~92 cluster contains six miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92) that can be grouped, based on sequence similarity, in four distinct subfamilies: miR-17 (includes miR-17 and miR-20a), miR-18, miR-19 (includes miR-19a and miR-19b), and miR-92a. During the past five years, supported by the NIH/NCI grant R01 CA149707, my group has performed a careful, and unprecedented, genetic dissection of this polycistronic cluster by generating an characterizing an allelic series of six genetically engineered mouse strains, each carrying selective targeted deletion of individual components of miR-17~92. This analysis, has lead to several important findings, including the discovery of causal role for miR-17 in skeletogenesis and axial patterning, the identification of germline mutations of miR- 17~92 as the cause of a human developmental syndrome known as Feingold Syndrome, and the discovery that the miR-19 family of miRNAs plays a key role in the pathogenesis of Myc-driven human cancers. These exciting new findings have lead to a series of novel hypotheses that are at the core of this grant renewal application. We propose a series of experiments that can be grouped into the following specific aims. The first aim has the goal of investigating the molecular mechanisms through which miR-19 contributes to Myc- driven tumorigenesis. We will also test the recently proposed hypothesis that miR-92 functionally antagonizes miR-19 by acting as a tumor suppressor. In the second aim, we will test a novel pharmacologic approach to inhibit miR-19 in vivo based on a recently developed technology that allows targeted delivery of miRNA antagonists to the acidic tumor microenvironment. In the third aim, we will develop a novel and more efficient method to experimentally identify miRNA-mRNA interactions directly in vivo. Successful completion of the experiments described in this grant application would greatly advance our understanding of this important miRNA cluster in particular, and of miRNAs in general, and could lead to novel anticancer approaches.

摘要