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MicroRNA and Transcription Factor Co-regulation in Cancer

癌症中的 MicroRNA 和转录因子共同调控

基本信息

批准号：
9329385
负责人：
Zhongming Zhao
金额：
$ 20.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-09 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9329385
关键词：
Biological Cancer Prognosis Clinical Colon Carcinoma Colorectal Cancer Complex Data Data Set Development Diagnosis Disease Ethnic Origin Foundations Freezing Gender Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genomics Glioblastoma Heterogeneity Investigation Knowledge Literature Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Messenger RNA Meta-Analysis MicroRNAs Modeling Molecular Profiling National Human Genome Research Institute Normal tissue morphology Oncogenes Output Pathogenesis Pathway Analysis Patients Pilot Projects Prevention Procedures Property Publishing Regulation Regulator Genes Reporting Role Sampling Seeds Statistical Methods System The Cancer Genome Atlas Therapeutic Time Tissues Tumor Suppressor Proteins Validation cancer biomarkers cancer cell cancer diagnosis cancer subtypes cancer type cell type cohort computer framework established cell line evidence base experimental study genome-wide innovation insight novel outcome forecast public health relevance success therapeutic target tool transcription factor transcriptome transcriptomics treatment response treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Recent studies have implicated the critical roles of microRNAs (miRNAs) in the pathogenesis of cancer, suggesting that miRNAs can be clinically useful as biomarkers for cancer prognosis, diagnosis and treatment. To date, the miRNA information in cancer studies has varied greatly due to data heterogeneity and disease complexity. In this application, in Aim 1, we will develop novel statistical methods to systematically perform meta- analysis of miRNA expression in the first four cancers (glioblastoma, ovarian cancer, colorectal cancer, and lung cancer) reported by The Cancer Genome Atlas (TCGA) project. For each of these cancers, more than 300 dysregulated miRNAs have been reported, which makes this aim not only feasible but immediately needed. In Aim 2, we will develop innovative strategies to explore miRNAs' functions in cancer through miRNA and transcription factor (TF) co-regulatory network analysis. For each cancer, we will build cancer-specific regulatory networks using miRNA/mRNA co-expression profiling and TF/gene regulation derived from the corresponding TCGA dataset. We will then identify network modules that reflect miRNA and TF co-regulation in cancer. We will investigate both common regulatory modules among four types of cancer and unique modules for each specific cancer. In Aim 3, we will experimentally validate selected miRNAs and their targets in common regulatory modules from Aim 2 using already available tissue and matched normal samples as well as established cell lines. This application will be the first systematic investigation of all available miRNA studes in the first four TCGA cancers. The successful completion of Aim 1 will provide us with a list of evidence-based miRNAs in glioblastoma, ovarian cancer, colorectal cancer, and lung cancer; the successful completion of Aim 2 will provide us with a comprehensive exploration of miRNA and TF co-regulation at the regulatory network level in these cancers; the successful completion of Aim 3 will validate our meta- and network- approaches, help us understand the miRNA regulatory mechanisms, and provide us with potential therapeutic targets in these cancers. Although quite exploratory, we expect this project is highly feasible and timely due to the large amount of data available in literature and from TCGA. This pioneering effort to detect functionally important miRNAs in complex diseases will greatly enhance our understanding of the regulatory systems in cancer, which will likely lead to the development of effective prevention, diagnosis, and treatment strategies.

描述（由申请人提供）：最近的研究表明 microRNA (miRNA) 在癌症发病机制中的关键作用，表明 miRNA 在临床上可用作癌症预后、诊断和治疗的生物标志物。迄今为止，由于数据异质性和疾病复杂性，癌症研究中的 miRNA 信息差异很大。在本应用的目标 1 中，我们将开发新的统计方法，系统地对癌症基因组图谱 (TCGA) 项目报告的前四种癌症（胶质母细胞瘤、卵巢癌、结直肠癌和肺癌）中的 miRNA 表达进行荟萃分析。对于这些癌症中的每一种，已经报道了超过 300 个失调的 miRNA，这使得这一目标不仅可行，而且是迫切需要的。在目标 2 中，我们将制定创新策略，通过 miRNA 和转录因子 (TF) 共调控网络分析来探索 miRNA 在癌症中的功能。对于每种癌症，我们将使用源自相应 TCGA 数据集的 miRNA/mRNA 共表达谱和 TF/基因调控来构建癌症特异性调控网络。然后我们将确定反映癌症中 miRNA 和 TF 共同调节的网络模块。我们将研究四种癌症的常见调节模块和每种特定癌症的独特模块。在目标 3 中，我们将使用现有组织和匹配的正常样本以及已建立的细胞系，通过实验验证目标 2 中常见调控模块中选定的 miRNA 及其靶标。该应用将是对前四种 TCGA 癌症中所有可用 miRNA 研究的首次系统研究。目标1的成功完成将为我们提供胶质母细胞瘤、卵巢癌、结直肠癌和肺癌中基于证据的miRNA列表； Aim 2的成功完成将为我们在这些癌症的调控网络水平上全面探索miRNA和TF的共同调控； Aim 3 的成功完成将验证我们的元方法和网络方法，帮助我们了解 miRNA 调控机制，并为我们提供这些癌症的潜在治疗靶点。尽管颇具探索性，但由于文献和 TCGA 提供了大量数据，我们预计该项目具有高度可行性和及时性。这项在复杂疾病中检测功能重要的 miRNA 的开创性努力将极大地增强我们对癌症调节系统的理解，这可能会导致有效预防、诊断和治疗策略的发展。