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Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease.

ABSTRACT: Identification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We define the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. Using pathway centrality, we identify mediating pathways in three pulmonary diseases (asthma; bronchopulmonary dysplasia (BPD); and chronic obstructive pulmonary disease (COPD)). We systematically evaluate the significance of all identified central pathways using genetic interactions. Mediating pathways shared by all three pulmonary disorders favor innate immune and inflammation-related processes, including toll-like receptor (TLR) signaling, PDGF- and angiotensin-regulated airway remodeling, the JAK-STAT signaling pathway, and interferon gamma. Disease-specific mediators, such as neurodevelopmental processes in BPD or adhesion molecules in COPD, are also highlighted. Some of our findings implicate pathways already in development as drug targets, while others may suggest new therapeutic approaches.

SUBMITTER: Park J

PROVIDER: S-EPMC6458310 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease.

Park Jisoo J Hescott Benjamin J BJ Slonim Donna K DK

Scientific reports 20190410 1

Identification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We define the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. Using pathway centrality, we identify mediating pathways in three pulmonary disea ...[more]

PMID: 30971743

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Project description:BACKGROUND: Cancers, a group of multifactorial complex diseases, are generally caused by mutation of multiple genes or dysregulation of pathways. Identifying biomarkers that can characterize cancers would help to understand and diagnose cancers. Traditional computational methods that detect genes differentially expressed between cancer and normal samples fail to work due to small sample size and independent assumption among genes. On the other hand, genes work in concert to perform their functions. Therefore, it is expected that dysregulated pathways will serve as better biomarkers compared with single genes. RESULTS: In this paper, we propose a novel approach to identify dysregulated pathways in cancer based on a pathway interaction network. Our contribution is three-fold. Firstly, we present a new method to construct pathway interaction network based on gene expression, protein-protein interactions and cellular pathways. Secondly, the identification of dysregulated pathways in cancer is treated as a feature selection problem, which is biologically reasonable and easy to interpret. Thirdly, the dysregulated pathways are identified as subnetworks from the pathway interaction networks, where the subnetworks characterize very well the functional dependency or crosstalk between pathways. The benchmarking results on several distinct cancer datasets demonstrate that our method can obtain more reliable and accurate results compared with existing state of the art methods. Further functional analysis and independent literature evidence also confirm that our identified potential pathogenic pathways are biologically reasonable, indicating the effectiveness of our method. CONCLUSIONS: Dysregulated pathways can serve as better biomarkers compared with single genes. In this work, by utilizing pathway interaction networks and gene expression data, we propose a novel approach that effectively identifies dysregulated pathways, which can not only be used as biomarkers to diagnose cancers but also serve as potential drug targets in the future.

Dataset Information

Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease.

Publications

Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease.

Similar Datasets

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