Individualized Medicine for Cardiomyopathies
Idiopathic dilated cardiomyopathy (DCM) is a heritable, progressive disorder that ultimately leads to heart failure. The development of effective therapy is significantly hindered by the heterogeneous nature of DCM. This manifests as both locus heterogeneity (mutations in different genes) and phenotypic variation (individuals with the same causative mutation exhibit highly variable phenotypes). While causative mutations have been identified in more than 50 genes, they account for less than half of heritable DCM cases. Even less is known about genetic modifiers that are presumably responsible for phenotypic variation. Therefore, discovering additional causative and modifier genes is critical for the development of individualized medicine for DCM.
The Zebrafish Genetics Laboratory is the first to establish several adult zebrafish models for cardiomyopathies, including acquired models for cardiomyopathies induced by anemia or doxorubicin, and inherited models for cardiomyopathies induced by genetic mutations in bag3 and lamp2. Using a transposon-based insertional mutagenesis screening platform, we demonstrated the feasibility of discovering genetic modifiers of cardiomyopathy via screening a zebrafish insertional cardiac (ZIC) mutant collection. While deleterious modifiers such as dnajb6 and sorbs2 suggest new cardiomyopathy genetic factors, salutary modifiers such as mtor and rxraa directly prompt novel therapeutic target genes.
Our research is expanding our collection of ZIC mutants to identify additional genetic modifiers and to develop new therapeutic strategies. We are also assessing these therapeutic strategies in zebrafish models for different types of cardiomyopathy, aiming to develop individualized medicine for human cardiomyopathies.