Aggregation and Contextualization of Murine Investigations Improves Discovery of Significant Human Atherosclerotic Cardiovascular Disease Associations

Le résumé fourni par la source

Preclinical murine models are foundational for investigating pathobiologic mechanisms.Despite decades of preclinical studies, the promise of linking specific genes identified in these studies to human disease mechanisms and novel therapies remains largely unfulfilled.1,2 One prominent example is atherosclerosis, the leading cause of death in humans.3 Unlike wild-type mice, mice with total body deletion of apolipoprotein-E (ApoE-KO) or low density lipoprotein receptor (LDLR-KO) develop atherosclerotic plaques.After more than 10,000 peer-reviewed publications, preclinical findings have had a modest impact on the clinical management of human atherosclerosis. 1 We reported a proof-of-concept study describing the Preclinical Science Integration and Translation (PRESCIANT) method that uses a systems biology approach to study the broader biologic context of gene perturbations modulating atherosclerosis in preclinical models and their relevance to human disease.4 We apply PRESCIANT to compare the fidelity of ApoE-KO and LDLR-KO models to identify human disease associations and test whether translation of preclinical findings is enhanced by integration and biologic contextualization. MethodsThe data for this study are available from the corresponding author upon reasonable request.

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