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Network medicine analysis of chondrocyte proteins towards new treatments of osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is a progressive disorder with high incidence in the ageing human population that still has no treatment currently. This disorder induces the breakdown of articular cartilage, leading to the exposure and damage of bone surfaces. For a global understanding of OA development, the systematic integration of known OA-related proteins with protein-protein interaction (PPI) networks is required. In this work, the OA-related interactome was reconstructed using multiple data sources to have the most up-to-date information on OA-related proteins and their interactions. We then combined emergent concepts in network medicine to detect new unclassified OA-related proteins. The mapping of known OA-related proteins with PPI networks showed that these proteins are locally connected to each other and agglomerated in a large component. To expand this module, we applied a diffusion-based algorithm that probabilistically induces more searches in the vicinity of the seed OA-related proteins. As a result, the 10 topmost ranked proteins were connected to the OA disease module, supporting the local hypothesis. We computed structural modules and selected those that had the highest enrichment of OA-related proteins. The identified molecules show a link between structural topology and disease dysfunctionality. Interestingly, the protein Q6EEV6 was highlighted for OA association by both methods, reinforcing the potential involvement of this protein. These results suggest that similar disease-connected modules may exist in different human disorders, which could lead to systematic identification of genes or proteins that have a joint role in specific disease phenotypes.

SUBMITTER: Nacher JC

PROVIDER: S-EPMC3906943 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Network medicine analysis of chondrocyte proteins towards new treatments of osteoarthritis.

Nacher Jose C JC Keith Benjamin B Schwartz Jean-Marc JM

Proceedings. Biological sciences 20140115 1778

Osteoarthritis (OA) is a progressive disorder with high incidence in the ageing human population that still has no treatment currently. This disorder induces the breakdown of articular cartilage, leading to the exposure and damage of bone surfaces. For a global understanding of OA development, the systematic integration of known OA-related proteins with protein-protein interaction (PPI) networks is required. In this work, the OA-related interactome was reconstructed using multiple data sources t ...[more]

PMID: 24430851

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Project description:Network medicine relies on different types of networks: from the molecular level of protein?protein interactions to gene regulatory network and correlation studies of gene expression. Among network approaches based on the analysis of the topological properties of protein?protein interaction (PPI) networks, we discuss the widespread DIAMOnD (disease module detection) algorithm. Starting from the assumption that PPI networks can be viewed as maps where diseases can be identified with localized perturbation within a specific neighborhood (i.e., disease modules), DIAMOnD performs a systematic analysis of the human PPI network to uncover new disease-associated genes by exploiting the connectivity significance instead of connection density. The past few years have witnessed the increasing interest in understanding the molecular mechanism of post-transcriptional regulation with a special emphasis on non-coding RNAs since they are emerging as key regulators of many cellular processes in both physiological and pathological states. Recent findings show that coding genes are not the only targets that microRNAs interact with. In fact, there is a pool of different RNAs-including long non-coding RNAs (lncRNAs) -competing with each other to attract microRNAs for interactions, thus acting as competing endogenous RNAs (ceRNAs). The framework of regulatory networks provides a powerful tool to gather new insights into ceRNA regulatory mechanisms. Here, we describe a data-driven model recently developed to explore the lncRNA-associated ceRNA activity in breast invasive carcinoma. On the other hand, a very promising example of the co-expression network is the one implemented by the software SWIM (switch miner), which combines topological properties of correlation networks with gene expression data in order to identify a small pool of genes-called switch genes-critically associated with drastic changes in cell phenotype. Here, we describe SWIM tool along with its applications to cancer research and compare its predictions with DIAMOnD disease genes.

Dataset Information

Network medicine analysis of chondrocyte proteins towards new treatments of osteoarthritis.

Publications

Network medicine analysis of chondrocyte proteins towards new treatments of osteoarthritis.

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