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Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms
- Source :
- JCI INSIGHT, 4(11):027652. American Society for Clinical Investigation
- Publication Year :
- 2019
-
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 (Fbn1(mgR/mgR) mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABA(B) receptor agonist baclofen. Systemic administration of baclofen to Fbn1(mgR/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 Fbn1(mgR/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.
- Subjects :
- 0301 basic medicine
Marfan syndrome
MARFAN
PROGRESSION
Bioinformatics
Transgenic
DISEASE
Marfan Syndrome
chemistry.chemical_compound
Aortic aneurysm
Thoracic/drug therapy
0302 clinical medicine
Receptor
General Medicine
IDENTIFY
Aortic Aneurysm
Drug repositioning
Baclofen
Transcriptome/drug effects
030220 oncology & carcinogenesis
Systemic administration
Research Article
Systems pharmacology
musculoskeletal diseases
congenital, hereditary, and neonatal diseases and abnormalities
GENES
Aortic Aneurysm, Thoracic/drug therapy
INHIBITION
Mice, Transgenic
Thoracic aortic aneurysm
AORTIC-ANEURYSM
03 medical and health sciences
Drug Repositioning/methods
medicine
Animals
Humans
Aortic Aneurysm, Thoracic
RECEPTOR
Animal
business.industry
Gene Expression Profiling
Drug Repositioning
Cardiovascular Agents
medicine.disease
EXPRESSION SIGNATURES
Disease Models, Animal
MICE
030104 developmental biology
chemistry
Cardiovascular Agents/pharmacology
Disease Models
Marfan Syndrome/complications
Transcriptome
business
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Database :
- OpenAIRE
- Journal :
- JCI INSIGHT, 4(11):027652. American Society for Clinical Investigation
- Accession number :
- edsair.doi.dedup.....dcc854adf7edabc91dc15990a05ecbe9