High-throughput functional in vivo evaluation of heart failure associated genes and pathways by Morpholino knock-down in zebrafish

Coordinator:    PD Dr. med Wolfgang Rottbauer
Institution: Abteilung Innere Medizin III, Uniklinik Heidelberg 
Despite the immense medical and economic interests the genetic causes of heart failure are mostly unknown.
The goal of the proposed research is to characterize the in vivo function of genomic regions found to be associated with human heart failure sub-phenotypes by gene knockdown and over-expression experiments in zebrafish. These experiments are essential to define within associated genomic regions those gene variants that indeed modify the heart failure phenotypes, and hence will help to further dissect the genetics of heart failure.
In our population-based genome wide association studies on defined sub-phenotypes (left ventricular hypertrophy, diastolic dysfunction, systolic dysfunction, arrhythmia) of heart failure we expect to identify several robust genetic modifier loci. SNPs (Single Nucleotide Polymorphism) within the associated genomic regions often do not reside within the modifier gene itself but are rather associated with a haplotype block of varying size. Hence, to dissect which gene variant in the associated genomic region indeed acts as genetic modifier, information on the function of all genes in the associated region, on their expression, as well as on the functional consequence of the corresponding gene variants is essential.
Antisense-mediated gene knock-down and transient overexpression of gene variants in wildtype and null-backgrounds of the zebrafish are by now reliable assays that allow rapid and cost-effective functional genomic studies in vivo. Especially cardiac phenotypes such as ventricular hypertrophy, contractile dysfunction, and arrhythmias can be easily evaluated in the transparent and fast developing zebrafish larvae.
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