We propose to build a multidisciplinary Zebrafish Cardiac Development Research Center with a collaborative group of zebrafish developmental biologists, zebrafish cardiac physiologists, and experts in chromatin structure, genome-wide gene network profiling, bioengineering and bioinformatics. We will investigate gene regulatory networks at distinct steps in development that control normal cardiac development at multiple molecular levels. Several diverse perturbations of cardiac development will serve as "inputs" to assess changes in cardiac development gene regulatory networks, including genetic mutants and morphants, embryological cell lineage manipulations and pharmacological treatments. The "outputs" will be analyses of chromatin structure that regulates transcriptional programs, epigenetic modifications including DNA methylation and chromatin marks that contribute to transcriptional activation (H3K4me3) or transcriptional repression (H3K9me3, and H3K27me3), genome-wide gene expression profiles (including mRNAs, microRNAs, SINE RNAs, other small RNAs) and transcriptional regulators involved in the patterning, morphogenesis and physiology of cardiomyocytes during development. Bioinformatics comparisons of normal and a large number of aberrant profiles within zebrafish will uncover molecular signatures of cardiac developmental defects. This multi-layered molecular profiling of cardiac development has not been performed in any organism. As new candidate genes or other perturbations (including pharmacological or environmental) arise within the Cardiac Development Consortium and Pediatric Cardiac Genomics Consortium, they will be incorporated into this multi-layered molecular profiling program to rapidly obtain genome-wide molecular signatures. Our infrastructure will make these datasets readily accessible to the consortia for trans-species comparisons to uncover conserved molecular signatures relevant to human developmental heart defects.
Obtaining multi-layered molecular profiles of cardiac developmental defects will reveal the underlying causes of cardiac developmental defects, with the long term goal of applying these insights to treatment of children with heart defects.
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