110 Connectivity mapping: an advanced bioinformatics approach to predict A20-inducing small molecules to reduce inflammation

Barsden, R.; Elborn, J.S.; Schock, Bettina; Ennis, Marcus; Kelly, Catriona; Zhang, S.-D.

doi:10.1016/s1569-1993(14)60246-0

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“…The genes identified in CF were activating transcription factor 3, intercellular adhesion molecule-1, a member of the RAS oncogene family (RAB5C) and domain-containing protein (DENND4A). Quantitative RT-PCR analyses in CF and non-CF cell lines confirmed a reduced basal expression and a lower LPS-induced expression of these genes, similar to A20 in these genes [ 39 , 88 ]. Together with A20, these A20 associates then served as an input to the connectivity mapping process ( www.broadinstitute.org ) to predict small molecules already licensed for the use in humans that will enhance A20 expression.…”

Section: Drug Repositioning Connectivity Mapping and Making New Drugmentioning

confidence: 86%

“…Together we performed a compound search using gene expression connectivity mapping to identify existing drugs that could induce A20 expression [ 88 ]. A total of 53 individual gene array sample sets of airway epithelial cells from patients with and without CF from 6 independent public datasets were used.…”

Section: Drug Repositioning Connectivity Mapping and Making New Drugmentioning

confidence: 99%

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Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

et al. 2015

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Cystic fibrosis (CF) is a lifelong, inflammatory multi-organ disease and the most common lethal, genetic condition in Caucasian populations, with a median survival rate of 41.5 years. Pulmonary disease, characterized by infective exacerbations, bronchiectasis and increasing airway insufficiency is the most serious manifestation of this disease process, currently responsible for over 80% of CF deaths. Chronic dysregulation of the innate immune and host inflammatory response has been proposed as a mechanism central to this genetic condition, primarily driven by the nuclear factor κB (NF-κB) pathway. Chronic activation of this transcription factor complex leads to the production of pro-inflammatory cytokines and mediators such as IL-6, IL-8 and TNF-α. A20 has been described as a central and inducible negative regulator of NF-κB. This intracellular molecule negatively regulates NF-κB-driven pro-inflammatory signalling upon toll-like receptor activation at the level of TRAF6 activation. Silencing of A20 increases cellular levels of p65 and induces a pro-inflammatory state. We have previously shown that A20 expression positively correlates with lung function (FEV₁%) in CF. Despite improvement in survival rates in recent years, advancements in available therapies have been incremental. We demonstrate that the experimental use of naturally occurring plant diterpenes such as gibberellin on lipopolysaccharide-stimulated cell lines reduces IL-8 release in an A20-dependent manner. We discuss how the use of a novel bio-informatics gene expression connectivity-mapping technique to identify small molecule compounds that similarly mimic the action of A20 may lead to the development of new therapeutic approaches capable of reducing chronic airway inflammation in CF.

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Section: Drug Repositioning Connectivity Mapping and Making New Drugmentioning

confidence: 86%

Section: Drug Repositioning Connectivity Mapping and Making New Drugmentioning

confidence: 99%

Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

et al. 2015

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110 Connectivity mapping: an advanced bioinformatics approach to predict A20-inducing small molecules to reduce inflammation

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Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

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110 Connectivity mapping: an advanced bioinformatics approach to predict A20-inducing small molecules to reduce inflammation

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Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-&#954;B-Mediated Inflammation

Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-&#954;B-Mediated Inflammation

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Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation