Integrated systems biology approach identifies gene targets for endothelial dysfunction

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Citações na Scopus
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Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
GIUDICE, Girolamo
MODESTIA, Silvestre Massimo
ZALMAS, Lykourgos-Panagiotis
FANG, Yun
PETSALAKI, Evangelia
Citação
MOLECULAR SYSTEMS BIOLOGY, v.19, n.12, article ID e11462, 19p, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening, high content imaging and network analysis to prioritise key ED genes and identify a pro- and anti-ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro-ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti-ED network was enriched in hypoxia, angiogenesis and cancer-related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease-specific candidate drug targets for endothelial dysfunction. imageMulti-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.Multi-omics data integration of endothelial cells treated with mimics of major cardiovascular disease factors identified 81 putative endothelial dysfunction (ED) genes.Upon siRNA-mediated gene knockdown, 83% of ED gene candidates affected at least one ED phenotype (26 exacerbating and 31 ameliorating the ED phenotypes).The analyses reveal emergent properties of disease networks, distinguishing between adaptation and rewiring for survival and those associated with deregulation that can be targeted for ED treatment.An orthogonal drug screen on treated endothelial cells provided additional support for DUSP1, IL6 and CCL2 as putative targets for ED. Multi-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.image
Palavras-chave
data integration, drug targets, endothelial dysfunction, network analysis, systems biology
URI
https://observatorio.fm.usp.br/handle/OPI/57908
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCP
Artigos e Materiais de Revistas Científicas - LIM/13
Artigos e Materiais de Revistas Científicas - ODS/03