Deconstruction and in vivo functionalization of the ceRNA cancer network (PQ-11)

ceRNA癌症网络的解构和体内功能化（PQ-11）

基本信息

批准号：
8547042
负责人：
PIER PAOLO PANDOLFI
金额：
$ 33.94万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547042
关键词：
3&apos Untranslated Regions Address Alleles BRAF gene Biological Biology Cancer Biology Cells Code Development Dimensions Disease Foundations Functional RNA Gene Expression Profile Gene Expression Regulation Genes Genome Hand Human Human Genome In Vitro KRAS2 gene Knock-out Knockout Mice Language Light Luciferases Malignant Neoplasms Mammals Mediating Messenger RNA Methodology MicroRNAs Molecular Mus Mutation Oncogenes Oncogenic Organism PTEN gene Pathway interactions Phenotype Property Proteins Proto-Oncogenes Pseudogenes RNA Recurrence Regulation Regulator Genes Research Response Elements Role Series Testing Transcript Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated Regions Validation Yeasts base cancer genetics cancer type comparative drug discovery genome analysis high throughput analysis in vivo innovation insight malignant phenotype mouse model novel overexpression theories tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We have recently discovered a novel means of gene regulation whereby both protein-coding and non-coding RNAs are able to cross-talk through a new RNA language. In this new regulatory dimension, both protein-coding and non-coding RNAs (e.g. pseudogenes) can communicate with each other by competing for common microRNAs, hence acting as "competing endogenous RNAs" or ceRNAs. We have described several ceRNAs that regulate the tumor suppressor PTEN, thereby ascribing tumor suppressive functions to numerous cancer-unrelated mRNAs and non-coding RNAs. Moreover, we have developed a methodology to computationally predict ceRNAs for cancer-associated genes based upon the identity of their microRNA response elements (MREs), which are the foundation of this new language. This allows for the prediction and identification of novel putative tumor suppressors and oncogenes, and, critically, for the functionalization of the entire cancer-relevant transcriptome. We therefore propose to further characterize oncogenic and tumor suppressive ceRNA networks in vitro. Additionally, to explore the function of ceRNAs in basic biology in vivo, we have created a series of mouse models that express pseudogenes or 3'UTRs or lack established PTEN ceRNAs in an inducible manner. We will cross these mice to existing mouse models of cancer to characterize the contribution of ceRNAs to the malignant phenotype in vivo. We propose to address these outstanding questions pertaining to this new transformative biological dimension with the following specific aims: (1) to identify and functionally characteriz novel tumor suppressive PTEN ceRNAs as well as to analyze mouse models lacking bona fide PTEN ceRNAs such as ZEB2 and VHL; (2) to explore the effect of PTEN 3'UTR overexpression on the malignant phenotype elicited by either PTEN heterozygosity or overexpression of the PTEN targeting miR106b~25 cluster; (3) to analyze the ceRNA activity of the pseudogene BRAFps towards its ancestral gene, the proto-oncogene BRAF, in vitro and in vivo and its contribution to cancer development. We strongly believe that our application is both highly innovative and timely, with the potential to significantly further our understanding of this novel process of gene regulation in cancer genetics and biology.

描述（由申请人提供）：我们最近发现了一种新颖的基因调节手段，从而蛋白质编码和非编码RNA都能够通过新的RNA语言进行交叉。在这个新的调节维度中，蛋白质编码和非编码RNA（例如假基因）都可以通过竞争共同的microRNA来相互通信，因此用作“竞争性内源性RNA”或CERNAS。我们描述了几个调节肿瘤抑制剂PTEN的CERNA，从而将肿瘤抑制功能归因于许多与癌症无关的mRNA和非编码RNA。此外，我们开发了一种方法，以根据其microRNA响应元素（MRE）的身份（MRE）的身份来预测与癌症相关基因的CERNA，这是这种新语言的基础。这允许预测和鉴定新型推定的肿瘤抑制剂和癌基因，并批判性地将整个癌症与癌症相关的功能化转录组。因此，我们建议进一步表征体外的致癌和肿瘤抑制CERNA网络。此外，为了探索CERNA在体内基本生物学中的功能，我们创建了一系列小鼠模型，这些模型以诱导方式表达伪基因或3'UTR或缺乏已建立的PTEN CERNAS。我们将将这些小鼠跨越现有的癌症小鼠模型，以表征CERNAS对体内恶性表型的贡献。我们建议以以下特定目的解决与这个新的变革性生物学维度有关的这些杰出问题：（1）识别和功能表征新颖的肿瘤抑制性pten cernas，并分析缺乏真正的pten cernas（例如Zeb2和vhl）的小鼠模型；（2）探索PTEN 3'UTR过表达对靶向miR106b〜25簇的PTEN杂合性或过表达引起的恶性表型的影响；（3）分析假元素疗法的CERNA活性对其祖先基因，原始癌基因BRAF，体外和体内及其对癌症发展的贡献。我们坚信，我们的应用既具有高度创新性和及时，也有可能进一步了解我们对癌症遗传学和生物学基因调节过程的理解。