This proposal is submitted in response to and meets the requirements of PA-03-015, a 2 year, R21-based mechanism to support feasibility studies that employ the use of existing human biological specimens to test new hypotheses related to heart disorders. Congenital cardiac disease affects 1:1000 newborns and is a significant cause of morbidity and mortality in the general pediatric population. Important clues to the disruption of genes critical to the developing cardiovascular system have come from studies of patients with identifiable genomic rearrangements. Previous studies by the PI have identified a microdeletion in chromosome 22q that results in conotruncal malformations and a DiGeorge phenotype, but involves a novel set of genes. In the past few years, the zebrafish (Danio rerio) has emerged as a powerful model to study the developing cardiovascular system, one that allows rapid screening and generation of mutants, and is readily amenable to manipulation of gene expression. This project will utilize the zebrafish as a model of cardiovascular development to test the hypothesis that expression of critical genes located within the novel chromosome 22q interval, is disrupted and results in cardiovascular dysgenesis. The project involves a new collaborative effort between the PI and an established developmental biologist, and extends the findings obtained using the zebrafish developmental paradigm, to studies of patients with cardiac malformations. Thus, the program described here investigates the association between abnormal expression of specific genes and their contribution to the pathogenesis of congenital heart defects. Mutation studies of candidate genes will be conducted using an extensive repository of specimens and data collected for over a decade at the Children's Hospital of Philadelphia under SCOR and SCCOR programs in Pediatric Cardiology. This approach is designed to generate novel reagents and data for use in future independent basic and clinical research projects. ? ?
| Newbern, Jason; Zhong, Jian; Wickramasinghe, Rasika S et al. (2008) Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci U S A 105:17115-20 |
| Emanuel, Beverly S; Saitta, Sulagna C (2007) From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat Rev Genet 8:869-83 |
