Grant Number:	1R03CA167695-01A1 Interpret this number
Primary Investigator:	Zhao, Zhongming
Organization:	Vanderbilt University
Project Title:	Investigating Micrornas and Their Regulatory Networks in Glioblastoma
Fiscal Year:	2013

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. It is highly resistant to radiation and chemotherapy. Understanding its molecular mechanisms is critical in order to develop more effective treatments. Recent studies revealed that microRNAs (miRNAs) play critical roles in the pathogenesis of GBM. To date, more than 100 dysregulated miRNAs have been found in GBM from various miRNA expression studies, which provide us with astonishing insights into the patterns of miRNA expression in GBM. However, the results reported so far have been inconsistent, presenting a great challenge in deciphering the underlying miRNA regulatory mechanisms in GBM. Therefore, a systematic examination of previous miRNA data is immediately needed and executable. In this project, we will develop innovative strategies to identify functionally important miRNAs significantly associated with GBM in the context of miRNA regulatory networks. The project will start by prioritizing miRNAs through integrating results from multiple studies using a mixed effects model, then build GBM-specific regulatory networks comprised of weighted molecules, i.e. GBM miRNAs, GBM genes and human transcription factors (TFs), and finally perform dense module search (DMS) of the regulatory networks to detect functionally critical miRNAs in GBM regulatory networks. We propose three specific aims. (1) To develop a novel, statistical integrative framework for the meta-analysis of miRNA expression data from multiple studies using a mixed effects model. Compared to traditional pooled analysis, we will integrate all possible effect sizes of each miRNA into a mixed effects model and calculate a P-value as its overall effect size to GBM. (2) To develop a novel computational pipeline to construct GBM-specific miRNA- mediated regulatory networks consisting of GBM miRNAs, GBM genes, and TFs. (3) To develop a novel dense module search (DMS) algorithm for identifying functionally important miRNAs in GBM. In this DMS algorithm, a module is defined as a set of FFLs, each of which includes miRNA, gene(s), and TF, and their regulatory relationships. This project constitutes a pioneering effort to establish an integrative and comprehensive modeling framework, as well as practical computational methods for detecting functionally important miRNAs in complex diseases and demonstrates it in GBM. Successful completion of this project will greatly enhance our understanding of the regulatory systems in GBM, which will likely lead to the development of effective prevention, diagnosis, and treatment strategies.




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MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer.
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microRNA regulation in cancer: One arm or two arms?
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Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.
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Clinically relevant genes and regulatory pathways associated with NRASQ61 mutations in melanoma through an integrative genomics approach.
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Studying tumorigenesis through network evolution and somatic mutational perturbations in the cancer interactome.
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A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance.
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Quantitative network mapping of the human kinome interactome reveals new clues for rational kinase inhibitor discovery and individualized cancer therapy.
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VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.
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