Leveraging Variant-perturbed Gene Regulation to Support Precision Medicine in COPD

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Summary/Abstract Micro-ribonucleic acids (miRNAs) are crucial for normal lung development, lung health, and have been implicated in lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). In addition, recent studies have identified miRNAs as potential therapeutic targets for COPD. miRNAs play an important role in gene regulation. miRNAs act within a complex regulatory structure that involves other biological molecules, including transcription factors, proteins, messenger RNAs (mRNAs), and other epigenetic mechanisms, all of which may be under the influence of genetic variants. A number of genetic variants have been identified as important for COPD through Genome-Wide Association Studies (GWAS). However, substantial computational and methodological challenges impede both linking genetic variants to altered molecular mechanisms and identifying therapeutic interventions that can effectively target these mechanisms for clinical impact. Understanding the complex structure of gene regulation, including by and of miRNAs, and how it is altered in disease or in response to a genetic variant, is critical for developing effective, precision-medicine based therapeutic strategies in COPD. In this project, we hypothesize that network-based methods, which model the collective response of biological molecules, have the potential to identify novel therapeutic strategies for COPD. Our goal is to leverage the predictions made by regulatory network models in a Connectivity Map analysis to identify potential therapeutic interventions for COPD. To accomplish this goal, we will first develop a network approach to model regulation by and of miRNAs using existing mRNA and miRNA expression data from blood samples in COPDGene. We will also generate miRNA expression data in lung tissue from the Lung Tissue Research Consortium (LTRC). We will use these data to assess changes in miRNAs related to COPD and to quantify associations between miRNAs and genetic variants. Co-expression, regulatory, and genetic-association networks will be developed to support multi-Omics predictions relevant to COPD. Network analysis results will be analyzed in the context of drug response profiles from the Connectivity Map to identify potential treatment strategies. The outcome of this project will be a deeper understanding of the regulatory role of miRNAs in COPD, how disease-specific miRNA regulation is altered in the context of COPD GWAS variants, and predictions for novel therapeutic strategies for COPD. The methods developed in the project will also support the broader goal of developing precision-medicine strategies for COPD.