GSE179656 Phenotypic Screening  with Deep Learning Identifies HDAC6 Inhibitors as Cardioprotective Agents in Mouse Models of Dilated Cardiomyopathy 

Contributors : Jin Yang ; Francis Grafton ; Ana Budan ; Sara Ranjbarvaziri ; Farshad Farshidfar ; Marie Cho ; Emma Xu ; Jaclyn Ho ; Mahnaz Maddah ; Kevin E Loewke ; Julio Medina ; David Sperandio ; Snahel Patel ; Tim Hoey ; Mohammad A MandegarSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusDilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell –derived cardiomyocytes (iPSC-CMs) deficient in BCL2-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs with a phenotypic screen and deep learning. Using a library of 5500 bioactive compounds and siRNA validation, we identified that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiac-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3 E455K mice, HDAC6 inhibitors improved left ventricular eje...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research