DESCRIPTION:

Throracic Aortic Aneurysms (TAAs) are a major clinical feature of Marfan syndrome (MFS). It is associated with mutations in the MFN1 gene encoding the multifunctional extracellular matrix glycoprotein Fibrillin-1. TAAs are life-threatening pathologies characterized by progressive vessel dilations associated with smooth muscle (SMC) dysfunction, occasional localiized inflammatory infiltrates, and severe maladaptive extracellular matrix (ECM) remodelling that, together, predispose the arterial wall to dissection and rupture leading to premature death. For this geneset expression values were obtained from the GEO accession GSE128101, and the corresponding SRA study accession SRP188087. The control GEO sample accessions were GSM3673486, GSM3673487 and GSM3673488 (corresponding in the SRA to SRX5527666, SRX5527667 & SRX5527668) compared to the case GEO sample accessions GSM3673483, GSM3673484 and GSM3673485 (corresponding to SRA accessions SRX5527663, SRX552764 & SRX552765). Expression values were calculated by the method detailed in 'HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis' (Genome Biol. 2020, PMID: 32660516), and log base 2 of the fold change are presented with a FDR of <0.05. All ensembl gene ids were checked in MGI for duplicates. The strain background was C57BL/6J, and all mice were male and sacrificed at P16.

LABEL:

Upregulated genes from TAA tissues of Fbn1(mgR/mgR) MFS male mice compared to WT at P16

SCORE TYPE:

Effect

DATE ADDED:

2022-06-29

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

Jens Hansen, Josephine Galatioto, Cristina I Caescu, Pauline Arnaud, Rhodora C Calizo, Bart Spronck, Sae-Il Murtada, Roshan Borkar, Alan Weinberg, Evren U Azeloglu, Maria Bintanel-Morcillo, James M Gallo, Jay D Humphrey, Guillaume Jondeau, Catherine Boileau, Francesco Ramirez, Ravi Iyengar

TITLE:

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

JOURNAL:

JCI insight 06 2019, Vol 4, pp.

ABSTRACT:

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases. PUBMED: 31167969
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