SP 1

Functional genomics in zebrafish to dissect the molecular networks of heart failure

The molecular underpinnings of human heart failure (HF) are only poorly defined yet. The systematic identification of the molecular mechanisms underlying human HF is hindered particularly by the significant mortality and the low percentage of familial forms suitable for linkage studies, as well as the limited access to cardiac tissue of HF patients. Especially the use of genetic model organisms, such as mice and zebrafish, recently enabled us to systematically dissect the genetic etiology of HF. Over the last years we isolated in 2 large-scale zebrafish forward genetic mutagenesis screens a multiplicity of mutant HF zebrafish lines, characterized them phenotypically and molecularly in detail, identified in a large proportion the underlying genetic cause and verified the relevance in human HF.
Within this consortium SP1 aims to define the molecular network and potential drugable targets of HF using transcriptome analyses, functional genomics studies, as well as high-throughput compound screening in zebrafish.

• Specific aim 1 is to decipher the common molecular determinants of HF in zebrafish by subjecting large transcriptome and quantitative phenotype datasets of 30 HF zebrafish lines to bioinformatic network analysis in collaboration with SP5.
  
  

• Specific aim 2 is to define in collaboration with SP2, SP3 and SP5, the molecular network of HF that is conserved between zebrafish, mouse and human by systems biology analysis.
  
  

• Specific aim 3 is to validate the corresponding molecular network models by functional genomics approaches in zebrafish and subject to iterative rounds of bioinformatic analyses.
  
  
• Specific aim 4 is to establish and characterize zebrafish knock-out lines for selected human HF network components (nodal points) and subject them to therapeutical small compound screens.
  
  

• Specific aim 5 is to validate the HF relevance of gene variants and mutations isolated in SP3 by gene knock-down and overexpression in zebrafish.