NGFN-PLUS

Functional genomics in zebrafish to dissect the genetic causes of human myocardial disease

Coordinator:    PD Dr. med. Wolfgang Rottbauer
Institution: Abteilung Innere Medizin III, Uniklinik Heidelberg
Homepage: www.klinikum.uni-heidelberg.de
Despite intensive efforts the molecular causes of cardiac diseases such as dilated cardiomyopathy (DCM), usually associated with significant morbidity and mortality, are mostly unknown. For the profound dissection of novel genetic causes and pathways involved in the pathogenesis of cardiac diseases such as congenital heart disease, cardiomyopathies and arrhythmias, genetic animal models such as the zebrafish have proven extremely helpful.
The proposed research persues to characterize 40 novel ethylnitrosurea (ENU)-induced recessive heart failure zebrafish mutants structurally, functionally as well as molecularly, and to define their genetic defects by a positional cloning approach. Furthermore, we will determine the role of the mutant zebrafish genes in human heart failure by mutation screening in various patient cohorts and characterize the disease gene-associated molecular signalling pathways using RNA expression and protein-interaction assays. One main focus of our research is to identify by bioinformatic network analysis common molecular players (nodal genes) in the various zebrafish heart failure associated signalling pathways and to define on a cellular and sub-cellular level the impact of the identified nodal genes on cardiomyocyte hypertrophy, sarcomeric signalling, and calcium signalling. Additionally, we will test the effect of small compound libraries on zebrafish embryos mutant in nodal genes to identify compounds that modify these nodal points, and hence have potential as novel therapeutics for human heart failure.
Finally, systematic elucidation of direct or indirect genetic causes of heart failure, characterization of the gene-defect associated molecular pathways, and identification of the central control points (nodes), i.e. signalling proteins interconnecting and integrating these various genetic pathways either by experimental studies or by bioinformatic network analysis is crucial for the definition of potential “drugable” molecular targets of heart failure.
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