Department of Medical Therapeutics for Heart Failure
Our division was born in January, 2015 as a new research group of Department of Cardiovascular Medicine in Osaka University Graduate School of Medicine. Our goal is to develop a novel diagnostic tool or medical therapy for intractable cardiovascular diseases including advanced heart failure, using bidirectional approaches both from clinical information, clinical samples and from latest molecular biology techniques.
Research Aim
Development of medical therapy for intractable cardiovascular diseases, especially targeting advanced heart failure (idiopathic cardiomyopathy, storage disease, mitochondrial disease) which is refractory to standard pharmacological and non-pharmacological therapy.
Research Content
- Generation of Human Disease Model Recapitulating Inherited Cardiomyopathy
DCM is a heterogenous disease including end-stage HCM, arrhythmogenic cardiomyopathy and secondary cardiomyopathy. We identified a desmoglein-2-deficient cardiomyopathy in a patient initially diagnosed with idiopathic DCM. Patient derived iPSC-cardiomyocytes recapitulated abnormal desmosomal structures, abnormal electrical activities, and structural fragilities. Restoration of DSG2 via CRISPR/Cas9 genome editing or AAV-mediated gene replacement of DSG2 corrected the abnormal phenotypes (Hum Mol Genet. 2021 Jul 9;30(15):1384-1397). We generated isogenic iPSC-cardiomyocytes with a precisely modified dose of plakophilin-2, modeling reduced contractility and impaired desmosome assembly. We generated isogenic desmosome-imaging iPSC-cardiomyocytes and provided proof-of-concept of PKP2 gene replacement for plakophilin-2-deficiency (Stem Cell Reports. 2022 Feb 8;17(2):337-351). - Development of Upstream Therapy Targeting Molecular Basis of Inherited Cardiomyopathy
We provided evidence that adeno associated virus (AAV)-mediated gene delivery promoted homology-directed repair (HDR) and directly corrected the pathogenic genetic mutation in mouse neonatal cultured cardiomyocytes (Sci Rep. 2017 Aug 24;7(1):9363). AAV-mediated gene delivery promoted HDR in adult mouse heart tissues and enabled sarcomere imaging in human iPSC-cardiomyocytes (Sci Rep. 2020 Sep 18;10(1):15348). We established a rapid experimental protocol to generate isogenic patient-derived iPSCs by HDR (Methods Mol Biol. 2021;2320:235-245). - Functional analysis of heart failure-related molecule
We identified a negative regulator of cardiomyocyte hypertrophy via regulating RNA metabolism using comprehensive ChIP-sequence analysis (Sci Rep. 2016 Jun 27;6:28592). We are now promoting research targeting heart failure-related molecule identified by omics analysis.
